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TWI745643B - Bispecific hiv-1-neutralizing antibodies - Google Patents

Bispecific hiv-1-neutralizing antibodies Download PDF

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TWI745643B
TWI745643B TW107146176A TW107146176A TWI745643B TW I745643 B TWI745643 B TW I745643B TW 107146176 A TW107146176 A TW 107146176A TW 107146176 A TW107146176 A TW 107146176A TW I745643 B TWI745643 B TW I745643B
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大衛 何
堯興 黃
江 余
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紐約市哥倫比亞大學理事會
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Abstract

In various embodiments, the present invention relates generally to using bispecific antibodies in the prevention and treatment of HIV.

Description

雙專一性HIV-1-中和性抗體Bispecific HIV-1-neutralizing antibody

於各種實施方式中，本發明大體上係關於在HIV之預防及治療中使用雙專一性抗體。 序列表In various embodiments, the present invention generally relates to the use of bispecific antibodies in the prevention and treatment of HIV. Sequence Listing

本申請案含有序列表，其已以ASCII格式透過EFS-Web呈送且係特此以其完整內容以引用方式併入。該ASCII副本（於2017年12月21日建立）被命名為ADR-001CP_ST25.txt且大小係145,851位元組。This application contains a sequence listing, which has been submitted via EFS-Web in ASCII format and is hereby incorporated by reference in its complete content. The ASCII copy (created on December 21, 2017) is named ADR-001CP_ST25.txt and the size is 145,851 bytes.

使用抗體（Ab）的被動致免疫係被認可的感染性疾病之預防及治療方法。此方法可包括從自感染性疾病恢復的供者製備人類免疫球蛋白並利用如此製劑（其含有對感染性生物有專一性的Ab）以保護受者對抗相同的疾病。或者，治療性抗體可藉由以抗原致免疫小鼠並接著工程設計／人類化小鼠Ab成人類版本來製造。單株抗體（mAb）在物理特性及免疫化學反應性方面係同質的，且因此提供絕對專一性活性之可能性。The use of antibodies (Ab) to prevent and treat infectious diseases recognized by the passive immune system. This method may include preparing human immunoglobulin from a donor who has recovered from an infectious disease and using such a preparation (which contains an Ab specific for infectious organisms) to protect the recipient against the same disease. Alternatively, therapeutic antibodies can be produced by immunizing mice with antigens and then engineering/humanized mouse Abs into human versions. Monoclonal antibodies (mAbs) are homogeneous in terms of physical properties and immunochemical reactivity, and therefore provide the possibility of absolutely specific activity.

該專一性對於一些目標而言可最終為限制，因此醫師已開發出由二個的不同mAb之片段構成且與二個不同種類的抗原結合的「雙專一性」mAb。此（例如）促進與僅微弱地表現的抗原的結合。一些雙專一性mAb可刺激強烈的免疫反應，限制其等之臨床應用。一個最近的改善此結果的方法係「CrossMab」方法學，其為採取更類似天然抗體的結構的雙專一性抗體形式。This specificity may ultimately be a limitation for some goals, so physicians have developed a "dual specificity" mAb that is composed of fragments of two different mAbs and binds to two different types of antigens. This, for example, promotes binding to antigens that are only weakly expressed. Some bispecific mAbs can stimulate a strong immune response, limiting their clinical applications. A recent method to improve this result is the "CrossMab" methodology, which is a bispecific antibody format that adopts a structure more similar to natural antibodies.

對於產生供臨床使用的對抗病原體（諸如HIV）的高度有效力的雙專一性或二價抗體之可能性包括許多不確定性。HIV上的之低刺突密度及刺突結構可能妨礙抗體對HIV的二價結合（例如）且細胞表面錨定之幾何及空間之特徵尚未被充分界定。在HIV套膜上是否存在足夠的表位可及性亦未知。錨定至宿主細胞膜的CrossMab雙專一性抗體提供了改善的局部抗體濃度、依序及／或相互依存的進入步驟之靶向、及對於單價結合的補償的可能性。There are many uncertainties regarding the possibility of producing highly effective bispecific or bivalent antibodies against pathogens (such as HIV) for clinical use. The low spike density and spike structure on HIV may hinder the bivalent binding of antibodies to HIV (for example) and the geometric and spatial characteristics of cell surface anchoring have not been fully defined. It is also unknown whether there is sufficient epitope accessibility on the HIV mantle. The CrossMab bispecific antibody anchored to the host cell membrane provides the possibility of improved local antibody concentration, targeting of sequential and/or interdependent entry steps, and compensation for monovalent binding.

另，抗體之大規模商業製造仍為挑戰性的。例如，治療性抗體之製造往往需要在良好作業規範條件下使用極大的細胞培養接著為廣闊的純化步驟，因此造成極高的製造成本。其他限制（諸如差的不溶性、蛋白質聚集、及蛋白質不穩定性）亦可能造成抗體之製造無法達到最佳。In addition, the large-scale commercial production of antibodies is still challenging. For example, the manufacture of therapeutic antibodies often requires extremely large cell cultures followed by extensive purification steps under good working practices, which results in extremely high manufacturing costs. Other limitations (such as poor insolubility, protein aggregation, and protein instability) may also result in suboptimal antibody production.

因此，對於可輕易地以商業規模製造的治療上有效的HIV抗體仍然存在著需求。Therefore, there is still a need for therapeutically effective HIV antibodies that can be easily manufactured on a commercial scale.

於一個方面，本發明係關於用於中和HIV的雙專一性抗體。該雙專一性抗體包括第一及第二抗體之部分，其中該第一抗體與HIV套膜蛋白結合。於某些實施方式中，該第一抗體係選自PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、10E8及其變體。於某些實施方式中，該雙專一性抗體包括第二抗體之部分，其中該第二抗體與細胞膜蛋白質結合。例如，該第二抗體與細胞受體蛋白或細胞膜輔受體蛋白結合。於一個實施方式中，該第二抗體係選自CD4抗體、CCR5抗體及CXCR4抗體，諸如Pro 140、ibalizumab、515H7、或其變體。於各種實施方式中，該雙專一性抗體具有CrossMab形式。In one aspect, the present invention relates to bispecific antibodies for neutralizing HIV. The bispecific antibody includes parts of a first antibody and a second antibody, wherein the first antibody binds to the HIV mantle protein. In some embodiments, the first antibody system is selected from PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, 10E8 and variants thereof. In certain embodiments, the bispecific antibody includes a portion of a second antibody, wherein the second antibody binds to a cell membrane protein. For example, the second antibody binds to a cell receptor protein or a cell membrane co-receptor protein. In one embodiment, the second antibody system is selected from CD4 antibody, CCR5 antibody and CXCR4 antibody, such as Pro 140, ibalizumab, 515H7, or variants thereof. In various embodiments, the bispecific antibody has a CrossMab format.

於另一個方面，本發明提供雙專一性抗體，其包括第一抗體及第二抗體之部分，其中該第一抗體與HIV套膜蛋白結合且該第二抗體與細胞膜蛋白質結合。於各種實施方式中，該雙專一性抗體具有CrossMab形式。In another aspect, the present invention provides a bispecific antibody, which includes a portion of a first antibody and a second antibody, wherein the first antibody binds to the HIV mantle protein and the second antibody binds to the cell membrane protein. In various embodiments, the bispecific antibody has a CrossMab format.

於各種實施方式中，亦提供包括於本文中揭示的雙專一性抗體的醫藥組成物。該醫藥組成物可經調配以用於口服、鼻內、肺、皮內、透皮、皮下、肌內、腹膜內、或靜脈內遞送。In various embodiments, a pharmaceutical composition including the bispecific antibody disclosed herein is also provided. The pharmaceutical composition can be formulated for oral, intranasal, pulmonary, intradermal, transdermal, subcutaneous, intramuscular, intraperitoneal, or intravenous delivery.

於進一步的方面，提供用於中和HIV的方法。該等方法包括使一抗原結合位置與結合HIV套膜蛋白的雙專一性抗體接觸及使另一個抗原結合位置與結合細胞膜蛋白質的雙專一性抗體接觸的步驟。In a further aspect, a method for neutralizing HIV is provided. These methods include the steps of contacting one antigen binding site with a bispecific antibody that binds to HIV mantle proteins and contacting another antigen binding site with a bispecific antibody that binds to cell membrane proteins.

於另一個方面，亦提供用於治療被HIV感染的患者的方法。該方法包括將於本文中揭示的雙專一性抗體或醫藥組成物之任何者投予至該患者。於一個實施方式中，該患者係人類。In another aspect, methods for treating patients infected with HIV are also provided. The method includes administering to the patient any of the bispecific antibodies or pharmaceutical compositions disclosed herein. In one embodiment, the patient is a human.

本發明之實施方式提供HIV之抑制。於各種實行中，形成雙專一性抗體，各包括來自兩種不同親本抗體的重鏈及輕鏈組份。於各種實施方式中，一種親本抗體專一性地結合HIV，例如HIV套膜蛋白Env。於各種實施方式中，另一種親本抗體專一性結合細胞膜蛋白質，例如CD4及CCR5。Embodiments of the present invention provide suppression of HIV. In various implementations, bispecific antibodies are formed, each including heavy chain and light chain components from two different parent antibodies. In various embodiments, a parent antibody specifically binds HIV, such as the HIV mantle protein Env. In various embodiments, another parent antibody specifically binds to cell membrane proteins, such as CD4 and CCR5.

於各種實施方式中，本發明之雙專一性抗體（例如HIV CrossMab抗體）具有IgG分子之天然架構，但具有雙專一性。於雙專一性抗體中，來自兩種親本抗體之各者的重鏈及輕鏈被組合在一起，以提供其中抗原結合片段1（Fab1）及Fab2之抗原結合位置具有不同結合專一性的抗體。於某些實施方式中，該雙專一性抗體係CrossMab形式抗體，如於圖1顯示的。於CrossMab形式，一個重鏈包括「突球（knob）」結構及另一個重鏈包括對應的「孔洞（hole）」結構，且來自一個親本抗體的恆定結構域之位置（即CL及CH1）被轉換，其等一起確保在組裝期間重鏈及輕鏈之正確配對。In various embodiments, the bispecific antibody of the present invention (for example, the HIV CrossMab antibody) has the natural structure of an IgG molecule, but has bispecificity. In a bispecific antibody, the heavy and light chains from each of the two parent antibodies are combined to provide an antibody in which the antigen binding sites of antigen-binding fragment 1 (Fab1) and Fab2 have different binding specificities . In some embodiments, the crossMab format antibody of the bispecific antibody system is as shown in FIG. 1. In the CrossMab format, one heavy chain includes a "knob" structure and the other heavy chain includes a corresponding "hole" structure, and is derived from the position of the constant domain (ie CL and CH1) of a parent antibody It is converted, which together ensure the correct pairing of the heavy and light chains during assembly.

已顯示各種mAb會藉由靶向HIV套膜蛋白Env並與之結合來封阻HIV感染（圖2B及10）。此等mAb包括（例如）PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、及10E8。圖2B（自www.scripps.edu/news/press/2014/20140424hiv.html改編）闡明mAb PGT145如何靶向HIV病毒套膜gp120上的V1/V2表位；mAb PGT128如何靶向HIV gp120之V3柄區上的多醣類；mAb 3BNC117如何靶向HIV gp120之CD4結合位置；mAb 10E8如何靶向HIV gp41之近膜外部區域（membrane proximal external region，MPER）；及mAb PGT151如何靶向HIV gp120及HIV gp41兩者上的表位。Various mAbs have been shown to block HIV infection by targeting and binding to the HIV envelope protein Env (Figures 2B and 10). Such mAbs include, for example, PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, and 10E8. Figure 2B (adapted from www.scripps.edu/news/press/2014/20140424hiv.html) illustrates how mAb PGT145 targets the V1/V2 epitope on the HIV virus mantle gp120; how mAb PGT128 targets the V3 handle of HIV gp120 How does mAb 3BNC117 target the CD4 binding site of HIV gp120; how mAb 10E8 targets the membrane proximal external region (MPER) of HIV gp41; and how mAb PGT151 targets HIV gp120 and HIV Epitope on both gp41.

此外，已展示單株抗體Pro 140（「P140」）、Ibalizumab（「iMab」）及515H7會藉由分別靶向CCR5、CD4及CXCR4人類細胞膜蛋白質並與其等結合而封阻HIV感染（圖2A）。具體言之，圖2A展示iMab如何靶向CD4，其為在人類T細胞上表現的用於HIV-1進入的主要受體；及Pro 140如何靶向CCR5，用於透過CCR5向性HIV-1的HIV-1進入的輔受體。In addition, the monoclonal antibodies Pro 140 ("P140"), Ibalizumab ("iMab") and 515H7 have been shown to block HIV infection by targeting CCR5, CD4, and CXCR4 human cell membrane proteins, respectively (Figure 2A) . Specifically, Figure 2A shows how iMab targets CD4, which is the main receptor for HIV-1 entry expressed on human T cells; and how Pro 140 targets CCR5 for HIV-1 through CCR5 Co-receptor for HIV-1 entry.

雖然以下討論聚焦於針對Env及細胞膜蛋白質CD4及CCR5的雙專一性抗體之用途，但應瞭解此僅僅係為了易於呈現的目的，且針對任何HIV表位的任何合適的抗體及針對任何合適的細胞膜蛋白質的任何合適的抗體皆可使用且係在本發明之範圍內。Although the following discussion focuses on the use of bispecific antibodies against Env and cell membrane proteins CD4 and CCR5, it should be understood that this is only for ease of presentation, and any suitable antibody against any HIV epitope and against any suitable cell membrane Any suitable antibody to protein can be used and is within the scope of the present invention.

因此，於各種實施方式中，本發明提供靶向HIV Env蛋白質以及細胞膜蛋白質CCR5、CD4及／或CXCR4並與其等結合的雙專一性抗體。於某些實施方式中，該等雙專一性抗體包括得自（但不限於）PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、及／或10E8抗體及其等之變體的序列（例如重鏈及輕鏈序列）。Therefore, in various embodiments, the present invention provides bispecific antibodies that target HIV Env protein and cell membrane proteins CCR5, CD4, and/or CXCR4 and bind to them. In some embodiments, the bispecific antibodies include antibodies derived from (but not limited to) PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, and/or 10E8 antibodies and the like Sequences of variants (eg heavy chain and light chain sequences).

界定PGT145抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www.ncbi.nlm.nih.gov/protein/3U1S_H及http://www.ncbi.nlm.nih.gov/protein/3U1S_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the PGT145 antibody can, for example, be found at www.ncbi.nlm.nih.gov/protein/3U1S_H and http://www.ncbi.nlm.nih.gov/protein/, respectively 3U1S_L (the entire contents of which are incorporated into this article by reference) are found.

界定PG9抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov/protein/3U4E_H及www dot ncbi dot nlm dot nih dot gov/protein/3MUH_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the PG9 antibody can, for example, be found in www dot ncbi dot nlm dot nih dot gov/protein/3U4E_H and www dot ncbi dot nlm dot nih dot gov/protein/3MUH_L (these etc. The full content of this article is incorporated into this article by reference).

界定PGT128抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov /protein/3TYG_H及www dot ncbi dot nlm dot nih dot gov protein/3TYG_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy chain and light chain of the PGT128 antibody can, for example, be found in www dot ncbi dot nlm dot nih dot gov /protein/3TYG_H and www dot ncbi dot nlm dot nih dot gov protein/3TYG_L (the others), respectively The full content is incorporated into this article by reference) found.

界定PGT121抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov /protein/4FQC_H及www dot ncbi dot nlm dot nih dot gov/protein/4FQC_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the PGT121 antibody can, for example, be found in www dot ncbi dot nlm dot nih dot gov /protein/4FQC_H and www dot ncbi dot nlm dot nih dot gov/protein/4FQC_L (these etc.), respectively The full content of this article is incorporated into this article by reference).

界定10-1074抗體之重鏈及輕鏈的胺基酸序列可（例如）於Mouquet H.、等人, (2012) PNAS, 109(47): E3268-77（包括補充資訊）（其完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the 10-1074 antibody can, for example, be found in Mouquet H., et al., (2012) PNAS, 109(47): E3268-77 (including supplementary information) (full content Department is incorporated into this article by reference) found.

界定3BNC117抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov/protein/4LSV_H及www dot ncbi dot nlm dot nih dot gov/protein/4LSV_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy chain and light chain of the 3BNC117 antibody can, for example, be found at www dot ncbi dot nlm dot nih dot gov/protein/4LSV_H and www dot ncbi dot nlm dot nih dot gov/protein/4LSV_L (these etc. The full content of this article is incorporated into this article by reference).

界定VRC01抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov/protein/4LST_H及www dot ncbi dot nlm dot nih dot gov/protein/4LST_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the VRC01 antibody can, for example, be found in www dot ncbi dot nlm dot nih dot gov/protein/4LST_H and www dot ncbi dot nlm dot nih dot gov/protein/4LST_L (the others), respectively The full content of this article is incorporated into this article by reference).

界定PGT151抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov/protein/4NUG_H及www dot ncbi dot nlm dot nih dot gov/protein/4NUG_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the PGT151 antibody can, for example, be found at www dot ncbi dot nlm dot nih dot gov/protein/4NUG_H and www dot ncbi dot nlm dot nih dot gov/protein/4NUG_L (these The complete content of this article is incorporated into this article by reference).

界定4E10抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov/protein/4LLV_H及www dot ncbi dot nlm dot nih dot gov/protein/4LLV_L（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the 4E10 antibody can, for example, be found at www dot ncbi dot nlm dot nih dot gov/protein/4LLV_H and www dot ncbi dot nlm dot nih dot gov/protein/4LLV_L (these etc.), respectively The full content of this article is incorporated into this article by reference).

界定10E8抗體之重鏈及輕鏈的胺基酸序列可（例如）分別於www dot ncbi dot nlm dot nih dot gov/protein/4G6F_B及www dot ncbi dot nlm dot nih dot gov/protein/4G6F_D（其等之完整內容係以引用方式併入本文中）找到。The amino acid sequences that define the heavy and light chains of the 10E8 antibody can, for example, be found in www dot ncbi dot nlm dot nih dot gov/protein/4G6F_B and www dot ncbi dot nlm dot nih dot gov/protein/4G6F_D (these etc.), respectively The full content of this article is incorporated into this article by reference).

於某些實施方式中，該等雙專一性抗體包括得自（但不限於）P140、iMab（或其MV1變體）及／或515H7抗體及其變體的序列（例如重鏈及輕鏈序列）。Pro 140、iMab（或其MV1變體）、及515H7抗體之重鏈及輕鏈序列係（例如）於以下者進一步描述：Olson, W. C.等人, (1999) J Virol., 73(5):4145-55、Trkola, A.等人, (2001) J Virol., 75(2):579-88、美國專利案編號7,122,185、Burkly L. C.等人, (1992) J Immunol., 149(5):1779-87、Moore J. P.等人, (1992) J Virol., 66(8):4784-93、Reimann K. A.、等人, (1997) AIDS Res Hum Retroviruses, 13(11):933-43、國際專利公開案編號WO2014100139、及歐洲專利公開案編號EP2246364，其等各者之完整內容皆係以引用方式併入本文中。In certain embodiments, the bispecific antibodies include sequences derived from (but not limited to) P140, iMab (or MV1 variants) and/or 515H7 antibodies and variants thereof (such as heavy chain and light chain sequences) ). The heavy and light chain sequences of Pro 140, iMab (or its MV1 variant), and 515H7 antibodies (for example) are further described in: Olson, WC et al., (1999) J Virol., 73(5): 4145-55, Trkola, A. et al., (2001) J Virol., 75(2):579-88, U.S. Patent No. 7,122,185, Burkly LC et al., (1992) J Immunol., 149(5): 1779-87, Moore JP, et al., (1992) J Virol., 66(8):4784-93, Reimann KA, et al., (1997) AIDS Res Hum Retroviruses, 13(11):933-43, international patent Publication No. WO2014100139 and European Patent Publication No. EP2246364, the complete contents of each of which are incorporated herein by reference.

用於本文中，抗體「變體」係指一種抗體，其具有與其所源自的親本抗體之胺基酸序列不同的胺基酸序列。於各種實施方式中，該變體相較於其親本抗體具有一或多個胺基酸改變。As used herein, an antibody "variant" refers to an antibody that has an amino acid sequence that is different from the amino acid sequence of the parent antibody from which it is derived. In various embodiments, the variant has one or more amino acid changes compared to its parent antibody.

於各種實施方式中，本發明之雙專一性抗體包括來自PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、或10E8抗體或其等之變體之重鏈及輕鏈序列及來自P140、iMab（或其MV1變體）、或515H7抗體或其等之變體之重鏈及輕鏈序列。In various embodiments, the bispecific antibody of the present invention includes heavy and light chains derived from PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, or 10E8 antibodies or variants thereof Sequence and heavy chain and light chain sequences derived from P140, iMab (or its MV1 variant), or 515H7 antibody or its variants.

於例示性實施方式中，已構築一系列的HIV CrossMab抗體，包括但不限於（例如）145/MV1、117/MV1、128/MV1、10E8/MV1、145/P140、128/P140、117/P140、10E8/P140、10E8/α-Her2、10E8/X19、及4E10/P140。PGT145（「145」）、3BNC117（「117」）、PGT128（「128」）、及10E8係四種不同的HIV套膜抗體。Pro 140（“P140”）係與細胞表面受體CCR5結合的mAb。MV1係一種CD4抗體，其為mAb Ibalizumab（「iMab」；參見（例如）國際專利公開案編號WO2014100139，其完整內容係以引用方式併入本文中）之經修改變體。X19係抗細胞表面受體CXCR4（參見（例如）美國專利案編號8,329,178，其完整內容係以引用方式併入本文中）之抗體變體之一，其不與表現CXCR4的細胞結合（且因此係用作為非表面結合性對照組）。α-Her2係與在細胞上表現的Her2受體結合的mAb。許多此等CrossMab抗體相較於其等之親本抗體（即單株抗體MV1、145、117或10E8）會增加HIV中和之廣度。於各種實施方式中，本發明之雙專一性抗體相較於其等之親本抗體顯著地增加對於HIV的中和之效力。In an exemplary embodiment, a series of HIV CrossMab antibodies have been constructed, including but not limited to, for example, 145/MV1, 117/MV1, 128/MV1, 10E8/MV1, 145/P140, 128/P140, 117/P140 , 10E8/P140, 10E8/α-Her2, 10E8/X19, and 4E10/P140. PGT145 ("145"), 3BNC117 ("117"), PGT128 ("128"), and 10E8 are four different HIV mantle antibodies. Pro 140 ("P140") is a mAb that binds to the cell surface receptor CCR5. MV1 is a CD4 antibody that is a modified variant of mAb Ibalizumab ("iMab"; see, for example, International Patent Publication No. WO2014100139, the entire content of which is incorporated herein by reference). X19 is one of the antibody variants against the cell surface receptor CXCR4 (see, for example, U.S. Patent No. 8,329,178, the entire content of which is incorporated herein by reference), which does not bind to cells expressing CXCR4 (and therefore is Used as a non-surface binding control group). α-Her2 is a mAb that binds to the Her2 receptor expressed on cells. Many of these CrossMab antibodies increase the breadth of HIV neutralization compared to their parent antibodies (ie, monoclonal antibodies MV1, 145, 117, or 10E8). In various embodiments, the bispecific antibody of the present invention significantly increases the efficacy of neutralizing HIV compared to its parental antibody.

界定各種例示性HIV CrossMab抗體之重鏈及輕鏈的胺基酸序列係於以下顯示。The amino acid sequences that define the heavy and light chains of various exemplary HIV CrossMab antibodies are shown below.

145/MV1抗體： 界定145/MV1抗體之源自MV1的輕鏈的胺基酸序列- MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定145/MV1抗體之源自MV1的重鏈的胺基酸序列- MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定145/MV1抗體之源自PGT145的輕鏈的胺基酸序列- PGT145-LC（SEQ ID NO:3）： EVVITQSPLFLPVTPGEAASLSCKCSHSLQHSTGANYLAWYLQRPGQTPRLLIHLATHRASGVPDRFSGSGSGTDFTLKISRVESDDVGTYYCMQGLHSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定145/MV1抗體之源自PGT145的重鏈的胺基酸序列- PGT145-HC-Knob（SEQ ID NO:4）：QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQATGQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKHRLRDYFLYNEYGPNYEEWGDYLATLDVWGHGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK145/MV1 antibody: The amino acid sequence of the light chain derived from MV1 defining the 145/MV1 antibody-MV1-VLCH1 (SEQ ID NO:1): DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence of the heavy chain derived from MV1 defining the 145/MV1 antibody-MV1-HC-Hole-Cross (SEQ ID NO: 2): QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from PGT145 defining the 145/MV1 antibody-PGT145-LC (SEQ ID NO: 3): EVVITQSPLFLPVTPGEAASLSCKCSHSLQHSTGANYLAWYLQRPGQTPRLLIHLATHRASGVPDRFSGSGSGTDFTLKISRVESDDVGTYYCMQGLHSPWTFGQGTKVEIKRTTKTLTKVAAPSVFIFPPSDEQLKSGTASVVCLLKANNFYPREAKTLSVTASVVCLLKANNFYPREAKTLSVTASVVCLLKANNFYPREAKTLSVTDYKESVSSVSLQSGV Definition 145 / PGT145 MV1 is derived from the amino acid sequence of the heavy chain of the antibody of - PGT145-HC-Knob (SEQ ID NO: 4): QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQATGQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKHRLRDYFLYNEYGPNYEEWGDYLATLDVWGHGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

117/MV1抗體： 界定117/MV1抗體之源自MV1的輕鏈的胺基酸序列- MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定117/MV1抗體之源自MV1的重鏈的胺基酸序列- MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定117/MV1抗體之源自3BNC117的輕鏈的胺基酸序列- 3BNC117-LC（SEQ ID NO:5）： DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVFGQGTKVQVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定117/MV1抗體之源自3BNC117的重鏈的胺基酸序列- 3BNC117-HC-Knob（SEQ ID NO:6）： QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK117/MV1 antibody: The amino acid sequence of the light chain derived from MV1 defining the 117/MV1 antibody-MV1-VLCH1 (SEQ ID NO:1): DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence of the heavy chain derived from MV1 defining the 117/MV1 antibody-MV1-HC-Hole-Cross (SEQ ID NO: 2): QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from 3BNC117 defining the 117/MV1 antibody-3BNC117-LC (SEQ ID NO: 5): DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVFGQGTKVQVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVTSKVSAVSLQSGNSGL HQVSLQSGNSGLKNSG The amino acid sequence of the heavy chain derived from 3BNC117 defining the 117/MV1 antibody-3BNC117-HC-Knob (SEQ ID NO: 6): QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

128/MV1抗體： 界定128/MV1抗體之源自MV1的輕鏈的胺基酸序列- MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定128/MV1抗體之源自MV1的重鏈的胺基酸序列- MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定128/MV1抗體之源自PGT128的輕鏈的胺基酸序列- PGT128-LC（SEQ ID NO:7）： QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定128/MV1抗體之源自PGT128的重鏈的胺基酸序列- PGT128-HC-Knob（SEQ ID NO:8）： QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK128/MV1 antibody: The amino acid sequence of the light chain derived from MV1 defining the 128/MV1 antibody-MV1-VLCH1 (SEQ ID NO:1): DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence of the heavy chain derived from MV1 defining the 128/MV1 antibody-MV1-HC-Hole-Cross (SEQ ID NO: 2): QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from PGT128 defining the 128/MV1 antibody-PGT128-LC (SEQ ID NO: 7): QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVASTPSKQSNTECVASTVSYST The amino acid sequence of the heavy chain derived from PGT128 defining the 128/MV1 antibody-PGT128-HC-Knob (SEQ ID NO: 8): QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8/MV1抗體： 界定10E8/MV1抗體之源自MV1的輕鏈的胺基酸序列- MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8/MV1抗體之源自MV1的重鏈的胺基酸序列- MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8/MV1抗體之源自10E8的輕鏈的胺基酸序列- 10E8-LC（SEQ ID NO:9）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8/MV1抗體之源自10E8的重鏈的胺基酸序列- 10E8-HC-Knob（SEQ ID NO:10）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8/MV1 antibody: The amino acid sequence of the light chain derived from MV1 defining the 10E8/MV1 antibody-MV1-VLCH1 (SEQ ID NO:1): DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence of the heavy chain derived from MV1 defining the 10E8/MV1 antibody-MV1-HC-Hole-Cross (SEQ ID NO: 2): QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 10E8-derived light chain defining the 10E8/MV1 antibody-10E8-LC (SEQ ID NO: 9): YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKSYSLTGSTVSTVS The amino acid sequence of the 10E8-derived heavy chain defining the 10E8/MV1 antibody-10E8-HC-Knob (SEQ ID NO: 10): EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

Δ10E8/MV1抗體 界定Δ10E8/MV1抗體之源自MV1的輕鏈MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定Δ10E8/MV1抗體之源自MV1的重鏈MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定Δ10E8/MV1抗體之源自Δ 10E8的輕鏈Δ10E8-LC（SEQ ID NO:21）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定Δ10E8/MV1抗體之源自Δ 10E8的重鏈10E8-HC-Knob（SEQ ID NO:22）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGKΔ10E8/MV1 antibody The light chain MV1-VLCH1 (SEQ ID NO:1) derived from MV1 that defines the Δ10E8/MV1 antibody: DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The heavy chain MV1-HC-Hole-Cross (SEQ ID NO: 2) derived from MV1 that defines the Δ10E8/MV1 antibody: QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The Δ10E8-derived light chain Δ10E8-LC (SEQ ID NO: 21) that defines the Δ10E8/MV1 antibody: YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKLSTCGSTVSTVS The heavy chain 10E8-HC-Knob (SEQ ID NO: 22) derived from Δ10E8 that defines the Δ10E8/MV1 antibody: EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

151/MV1抗體 界定151/MV1抗體之源自MV1的輕鏈的胺基酸序列- MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定151/MV1抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定151/MV1抗體之源自PGT151的輕鏈PGT151-LC（SEQ ID NO:23）： DIVMTQTPLSLSVTPGQPASISCKSSESLRQSNGKTSLYWYRQKPGQSPQLLVFEVSNRFSGVSDRFVGSGSGTDFTLRISRVEAEDVGFYYCMQSKDFPLTFGGGTKVDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定151/MV1抗體之源自PGT151的重鏈PGT151-HC-Knob（SEQ ID NO:24）： RVQLVESGGGVVQPGKSVRLSCVVSDFPFSKYPMYWVRQAPGKGLEWVAAISGDAWHVVYSNSVQGRFLVSRDNVKNTLYLEMNSLKIEDTAVYRCARMFQESGPPRLDRWSGRNYYYYSGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK151/MV1 antibody The amino acid sequence of the light chain derived from MV1 defining the 151/MV1 antibody-MV1-VLCH1 (SEQ ID NO:1): DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 151/MV1 antibody: QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The light chain PGT151-LC (SEQ ID NO: 23) derived from PGT151 that defines the 151/MV1 antibody: DIVMTQTPLSLSVTPGQPASISCKSSESLRQSNGKTSLYWYRQKPGQSPQLLVFEVSNRFSGVSDRFVGSGSGTDFTLRISRVEAEDVGFYYCMQSKDFPLTFGGGTKVDLKRTVAAPSVFIFPPSDEQLSSEKGTASVVCLLNNFYPREATEKVQDSKDSQSLACESFGESLHKSLRQSLRQSNGKTSLYWYRQKPGQSPQLLVVTDFTLRISRVEAEDVGFYYCMQSKDFPLTFGGGTKVDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREATEKVQDSKDSV The heavy chain PGT151-HC-Knob (SEQ ID NO: 24) derived from PGT151 that defines the 151/MV1 antibody: RVQLVESGGGVVQPGKSVRLSCVVSDFPFSKYPMYWVRQAPGKGLEWVAAISGDAWHVVYSNSVQGRFLVSRDNVKNTLYLEMNSLKIEDTAVYRCARMFQESGPPRLDRWSGRNYYYYSGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

145/P140抗體： 界定145/P140抗體之源自Pro 140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定145/P140抗體之源自Pro 140的重鏈的胺基酸序列- PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定145/P140抗體之源自PGT145的輕鏈的胺基酸序列- PGT145-LC（SEQ ID NO:3）： EVVITQSPLFLPVTPGEAASLSCKCSHSLQHSTGANYLAWYLQRPGQTPRLLIHLATHRASGVPDRFSGSGSGTDFTLKISRVESDDVGTYYCMQGLHSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定145/P140抗體之源自PGT145的重鏈的胺基酸序列- PGT145-HC-Knob（SEQ ID NO:4）： QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQATGQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKHRLRDYFLYNEYGPNYEEWGDYLATLDVWGHGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK145/P140 antibody: The amino acid sequence of the Pro 140-derived light chain defining the 145/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the heavy chain derived from Pro 140 defining the 145/P140 antibody-PRO140-HC-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from PGT145 defining the 145/P140 antibody-PGT145-LC (SEQ ID NO: 3): EVVITQSPLFLPVTPGEAASLSCKCSHSLQHSTGANYLAWYLQRPGQTPRLLIHLATHRASGVPDRFSGSGSGTDFTLKISRVESDDVGTYYCMQGLHSPWTFGQGTKVEIKRTTKTLTKVAAPSVFIFPPSDEQLKSGTASVVCLLKANNFYPREAKTLSVTASVVCLLKANNFYPREAKTLSVTASVVCLLKANNFYPREAKTLSVTDYKESVSSVSLQSGV The amino acid sequence of the heavy chain derived from PGT145 defining the 145/P140 antibody-PGT145-HC-Knob (SEQ ID NO: 4): QVQLVQSGAEVKKPGSSVKVSCKASGNSFSNHDVHWVRQATGQGLEWMGWMSHEGDKTGLAQKFQGRVTITRDSGASTVYMELRGLTADDTAIYYCLTGSKHRLRDYFLYNEYGPNYEEWGDYLATLDVWGHGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

117/P140抗體： 界定117/P140抗體之源自Pro 140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定117/P140抗體之源自Pro 140的重鏈的胺基酸序列- PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定117/P140抗體之源自3BNC117的輕鏈的胺基酸序列- 3BNC117-LC（SEQ ID NO:5）： DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVFGQGTKVQVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定117/P140抗體之源自3BNC117的重鏈的胺基酸序列- 3BNC117-HC-Knob（SEQ ID NO:6）： QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK117/P140 antibody: The amino acid sequence of the light chain derived from Pro 140 defining the 117/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the heavy chain derived from Pro 140 defining the 117/P140 antibody-PRO140-HC-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from 3BNC117 defining the 117/P140 antibody-3BNC117-LC (SEQ ID NO: 5): DIQMTQSPSSLSASVGDTVTITCQANGYLNWYQQRRGKAPKLLIYDGSKLERGVPSRFSGRRWGQEYNLTINNLQPEDIATYFCQVYEFVVFGQGTKVQVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVQWKESVVCLLNNFYPREAKVTSKVSAVSLQSGNSGL HQVSLQSGNSGLKNSG The amino acid sequence of the heavy chain derived from 3BNC117 defining the 117/P140 antibody-3BNC117-HC-Knob (SEQ ID NO: 6): QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPKTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDYWDFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

128/P140抗體： 界定128/P140抗體之源自Pro 140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定128/P140抗體之源自Pro 140的重鏈的胺基酸序列- PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定128/P140抗體之源自PGT128的輕鏈的胺基酸序列- PGT128-LC（SEQ ID NO:7）： QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定128/P140抗體之源自PGT128的重鏈的胺基酸序列- PGT128-HC-Knob（SEQ ID NO:8）： QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK128/P140 antibody: The amino acid sequence of the light chain derived from Pro 140 defining the 128/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the heavy chain derived from Pro 140 defining the 128/P140 antibody-PRO140-HC-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from PGT128 defining the 128/P140 antibody-PGT128-LC (SEQ ID NO: 7): QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVASTPSKQSNTECVASTVSYST The amino acid sequence of the heavy chain derived from PGT128 defining the 128/P140 antibody-PGT128-HC-Knob (SEQ ID NO: 8): QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8/P140抗體： 界定10E8/P140抗體之源自Pro 140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8/P140抗體之源自Pro 140的重鏈的胺基酸序列- PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8/P140抗體之源自10E8的輕鏈的胺基酸序列- 10E8-LC（SEQ ID NO:9）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8/P140抗體之源自10E8的重鏈的胺基酸序列- 10E8-HC-Knob（SEQ ID NO:10）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8/P140 antibody: The amino acid sequence of the light chain derived from Pro 140 defining the 10E8/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the heavy chain derived from Pro 140 defining the 10E8/P140 antibody-PRO140-HC-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 10E8-derived light chain defining the 10E8/P140 antibody-10E8-LC (SEQ ID NO: 9): YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKSYSLTGSTVSTVS The amino acid sequence of the heavy chain derived from 10E8 defining the 10E8/P140 antibody-10E8-HC-Knob (SEQ ID NO: 10): EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

Δ10E8/P140抗體 界定Δ10E8/P140抗體之源自PRO140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定Δ10E8/P140抗體之源自PRO140的重鏈的胺基酸序列- PRO140-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定Δ10E8/P140抗體之源自Δ10E8輕鏈- Δ10E8-LC（SEQ ID NO:21）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定Δ10E8/P140抗體之源自Δ10E8重鏈- 10E8-HC-Knob（SEQ ID NO:22）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGKΔ10E8/P140 antibody The amino acid sequence of the PRO140-derived light chain defining the Δ10E8/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the PRO140-derived heavy chain defining the Δ10E8/P140 antibody-PRO140-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Define the Δ10E8/P140 antibody derived from the Δ10E8 light chain-Δ10E8-LC (SEQ ID NO: 21): YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKLSTCGSTVSTVS Define the Δ10E8/P140 antibody derived from the Δ10E8 heavy chain-10E8-HC-Knob (SEQ ID NO: 22): EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

151/P140抗體 界定151/P140抗體之源自PRO140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定151/P140抗體之源自PRO140的重鏈的胺基酸序列- PRO140-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定151/P140抗體之源自PGT151的輕鏈的胺基酸序列- PGT151-LC（SEQ ID NO:23）： DIVMTQTPLSLSVTPGQPASISCKSSESLRQSNGKTSLYWYRQKPGQSPQLLVFEVSNRFSGVSDRFVGSGSGTDFTLRISRVEAEDVGFYYCMQSKDFPLTFGGGTKVDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定151/P140抗體之源自PGT151的重鏈的胺基酸序列- PGT151-HC-Knob（SEQ ID NO:24）： RVQLVESGGGVVQPGKSVRLSCVVSDFPFSKYPMYWVRQAPGKGLEWVAAISGDAWHVVYSNSVQGRFLVSRDNVKNTLYLEMNSLKIEDTAVYRCARMFQESGPPRLDRWSGRNYYYYSGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK151/P140 antibody The amino acid sequence of the PRO140-derived light chain defining the 151/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK Defining the amino acid sequence of the PRO140-derived heavy chain of the 151/P140 antibody-PRO140-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from PGT151 defining the 151/P140 antibody-PGT151-LC (SEQ ID NO: 23): DIVMTQTPLSLSVTPGQPASISCKSSESLRQSNGKTSLYWYRQKPGQSPQLLVFEVSNRFSGVSDRFVGSGSGTDFTLRISRVEAEDVGFYYCMQSKDFPLTFGGGTKVDLKRTVAAPSVFIFPPSDEQLSSEKGTASVVCLLNNFYPREATEKVQDSKDSQSLACESFGESLHKSLRQSLRQSNGKTSLYWYRQKPGQSPQLLVVTDFTLRISRVEAEDVGFYYCMQSKDFPLTFGGGTKVDLKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREATEKVQDSKDSV The amino acid sequence of the heavy chain derived from PGT151 defining the 151/P140 antibody-PGT151-HC-Knob (SEQ ID NO: 24): RVQLVESGGGVVQPGKSVRLSCVVSDFPFSKYPMYWVRQAPGKGLEWVAAISGDAWHVVYSNSVQGRFLVSRDNVKNTLYLEMNSLKIEDTAVYRCARMFQESGPPRLDRWSGRNYYYYSGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8/α-Her2抗體： 界定10E8/α-Her2抗體之源自α-Her2的輕鏈的胺基酸序列- antiHer2-VLCH1（SEQ ID NO:13）： DIVMTQSHKFMSTSVGDRVSITCKASQDVNTAVAWYQQKPGHSPKLLIYSASFRYTGVPDRFTGNRSGTDFTFTISSVQAEDLAVYYCQQHYTTPPTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8/α-Her2抗體之源自α-Her2的重鏈的胺基酸序列- antiHer2-HC-Hole-Cross（SEQ ID NO:14）： QVQLQQSGPELVKPGASLKLSCTASGFNIKDTYIHWVKQRPEQGLEWIGRIYPTNGYTRYDPKFQDKATITADTSSNTAYLQVSRLTSEDTAVYYCSRWGGDGFYAMDYWGQGASVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8/α-Her2抗體之源自10E8的輕鏈的胺基酸序列- 10E8-LC（SEQ ID NO:9）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8/α-Her2抗體之源自10E8的重鏈的胺基酸序列- 10E8-HC-Knob（SEQ ID NO:10）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8/α-Her2 antibody: The amino acid sequence of the light chain derived from α-Her2 defining the 10E8/α-Her2 antibody-antiHer2-VLCH1 (SEQ ID NO: 13): DIVMTQSHKFMSTSVGDRVSITCKASQDVNTAVAWYQQKPGHSPKLLIYSASFRYTGVPDRFTGNRSGTDFTFTISSVQAEDLAVYYCQQHYTTPPTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFQVLQVSSVPSKNTPKVTVSWNSGALTSGVHTFQVLQSVKKVESLK The amino acid sequence of the heavy chain derived from α-Her2 defining the 10E8/α-Her2 antibody-antiHer2-HC-Hole-Cross (SEQ ID NO: 14): QVQLQQSGPELVKPGASLKLSCTASGFNIKDTYIHWVKQRPEQGLEWIGRIYPTNGYTRYDPKFQDKATITADTSSNTAYLQVSRLTSEDTAVYYCSRWGGDGFYAMDYWGQGASVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 10E8-derived light chain defining the 10E8/α-Her2 antibody-10E8-LC (SEQ ID NO: 9): YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKSYSLTGSTVSTVS The amino acid sequence of the heavy chain derived from 10E8 defining the 10E8/α-Her2 antibody-10E8-HC-Knob (SEQ ID NO: 10): EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

4E10/P140抗體： 界定4E10/P140抗體之源自Pro 140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定4E10/P140抗體之源自Pro 140的重鏈的胺基酸序列- PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定4E10/P140抗體之源自4E10的輕鏈的胺基酸序列- 4E10-LC（SEQ ID NO:17）： EIVLTQSPGTQSLSPGERATLSCRASQSVGNNKLAWYQQRPGQAPRLLIYGASSRPSGVADRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGQSLSTFGQGTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 界定4E10/P140抗體之源自4E10的重鏈的胺基酸序列- PGT145-HC-Knob（SEQ ID NO:18）： QVQLVQSGAEVKRPGSSVTVSCKASGGSFSTYALSWVRQAPGRGLEWMGGVIPLLTITNYAPRFQGRITITADRSTSTAYLELNSLRPEDTAVYYCAREGTTGAGWLGKPIGAFAHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK4E10/P140 antibody: The amino acid sequence of the Pro 140-derived light chain defining the 4E10/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the heavy chain derived from Pro 140 defining the 4E10/P140 antibody-PRO140-HC-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 4E10-derived light chain defining the 4E10/P140 antibody-4E10-LC (SEQ ID NO: 17): EIVLTQSPGTQSLSPGERATLSCRASQSVGNNKLAWYQQRPGQAPRLLIYGASSRPSGVADRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGQSLSTFGQGTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVKESVVVCLLQSGNSGLACESGVSLQSGNSGLSHQVSLQSGNSGLVTKSQVSLQSGNSQTLSKVTASVVVCLLQSGNSGLKVSL The amino acid sequence of the 4E10-derived heavy chain defining the 4E10/P140 antibody-PGT145-HC-Knob (SEQ ID NO: 18): QVQLVQSGAEVKRPGSSVTVSCKASGGSFSTYALSWVRQAPGRGLEWMGGVIPLLTITNYAPRFQGRITITADRSTSTAYLELNSLRPEDTAVYYCAREGTTGAGWLGKPIGAFAHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8/X19抗體： 界定10E8/X19抗體之源自X19的輕鏈的胺基酸序列- X19-VLCH1（SEQ ID NO:19）： EIVLTQSPATLSVSPGRRATLSCRASQSVNTNLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSPLTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8/X19抗體之源自X19的重鏈的胺基酸序列- X19-HC-Hole-Cross（SEQ ID NO:20）： QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYPMHWVRQAPGKGLEWMTVISSDGRNKYYPDSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCARGGYHDFWSGPDYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8/X19抗體之源自10E8的輕鏈的胺基酸序列- 10E8-LC（SEQ ID NO:9）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8/X19抗體之源自10E8的重鏈的胺基酸序列- PGT145-HC-Knob（SEQ ID NO:10）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8/X19 antibody: The amino acid sequence of the X19-derived light chain defining the 10E8/X19 antibody-X19-VLCH1 (SEQ ID NO: 19): EIVLTQSPATLSVSPGRRATLSCRASQSVNTNLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQHYGSSPLTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKTYFPEPKKVEVTVSWNSGALTSGVHTFQVLQSSVSCLYSCL The amino acid sequence of the X19-derived heavy chain defining the 10E8/X19 antibody-X19-HC-Hole-Cross (SEQ ID NO: 20): QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYPMHWVRQAPGKGLEWMTVISSDGRNKYYPDSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCARGGYHDFWSGPDYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 10E8-derived light chain defining the 10E8/X19 antibody-10E8-LC (SEQ ID NO: 9): YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKSYSLTGSTVSTVS The amino acid sequence of the heavy chain derived from 10E8 defining the 10E8/X19 antibody-PGT145-HC-Knob (SEQ ID NO: 10): EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8/515H7抗體 界定10E8/515H7抗體之源自515H7的輕鏈的胺基酸序列– 515H7-VLCH1（SEQ ID NO:25）： DIVMSQSPSSLAVSAGEKVTMSCKSSQSLFNSRTRKNYLAWYQQKPGQSPKLLIYWASARDSGVPARFTGSGSETYFTLTISRVQAEDLAVYYCMQSFNLRTFGGGTKLEIKASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8/515H7抗體之源自515H7的重鏈的胺基酸序列– 515H7-Hole-Cross（SEQ ID NO:26）： EVNLVESGGGLVQPGGSLRLSCATSGFTFTDNYMSWVRQPPGKALEWLGFIRNKANGYTTDYSASVRGRFTISRDNSQSILYLQMNALRAEDSATYYCARDVGSNYFDYWGQGTTLTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8/515H7抗體之源自10E8的輕鏈的胺基酸序列- 10E8-LC（SEQ ID NO:9）： YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8/515H7抗體之源自10E8的重鏈的胺基酸序列- 10E8-HC-Knob（SEQ ID NO:10）： EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8/515H7 antibody The amino acid sequence of the light chain derived from 515H7 that defines the 10E8/515H7 antibody-515H7-VLCH1 (SEQ ID NO: 25): DIVMSQSPSSLAVSAGEKVTMSCKSSQSLFNSRTRKNYLAWYQQKPGQSPKLLIYWASARDSGVPARFTGSGSETYFTLTISRVQAEDLAVYYCMQSFNLRTFGGGTKLEIKASTKSSQSLFNSRTRKNYLAWYQQKPGQSPKLLIYWASARDSGVPARFTGSGSETYFTLTISRVQAEDLAVYYCMQSFNLRTFGGGTKLEIKASTKASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWTYVQVSGVPSKSCKN The amino acid sequence of the heavy chain derived from 515H7 that defines the 10E8/515H7 antibody-515H7-Hole-Cross (SEQ ID NO: 26): EVNLVESGGGLVQPGGSLRLSCATSGFTFTDNYMSWVRQPPGKALEWLGFIRNKANGYTTDYSASVRGRFTISRDNSQSILYLQMNALRAEDSATYYCARDVGSNYFDYWGQGTTLTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 10E8-derived light chain defining the 10E8/515H7 antibody-10E8-LC (SEQ ID NO: 9): YELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKSYSLTGSTVSTVS The amino acid sequence of the heavy chain derived from 10E8 defining the 10E8/515H7 antibody-10E8-HC-Knob (SEQ ID NO: 10): EVQLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQPPGKGLEWVGRITGPGEGWSVDYAAPVEGRFTISRLNSINFLYLEMNNLRMEDSGLYFCARTGKYYDFWSGYPPGEEYFQDWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

嵌合CDR123抗體（SEQ ID NO:27）： SELTQDPAVSVALGQTVRITCRGDSLRSHYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSChimeric CDR123 antibody (SEQ ID NO: 27): SELTQDPAVSVALGQTVRITCRGDSLRSHYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWASSYDSSPVPEGVYPGAVTVAWASSYDSSPVPEGVTPSKSYSTECVAPVLVIYGKNNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADy

嵌合FW123（SEQ ID NO:28）： YELTQETGVSVALGRTVTITCQGDSLRSYYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCNSRDSSGNHLVVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSChimeric FW123 (SEQ ID NO: 28): YELTQETGVSVALGRTVTITCQGDSLRSYYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCNSRDSSGNHLVVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWASSYLSLTVPEGVTPSKSYSTSVPEQYATSTVSYSTVPAQTSTVSTV

10E8V1.0/iMab抗體 界定10E8v1.0/MV1抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8v1.0/MV1抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8v1.0/iMab抗體之源自10E8v1.0的輕鏈的胺基酸序列- 10E8v1.0-LC（SEQ ID NO:29）： ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8v1.0/iMab抗體之源自10E8v1.0的重鏈的胺基酸序列- 10E8v1.0-HC-Knob（SEQ ID NO:30）： EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V1.0/iMab antibody The amino acid sequence MV1-VLCH1 (SEQ ID NO:1) of the light chain derived from MV1 that defines the 10E8v1.0/MV1 antibody: DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8v1.0/MV1 antibody: QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the 10E8v1.0-derived light chain defining the 10E8v1.0/iMab antibody-10E8v1.0-LC (SEQ ID NO: 29): ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGQSYSETTVAPTVSTVHRGSKSYSTEVKANKSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPD The amino acid sequence of the heavy chain derived from 10E8v1.0 defining the 10E8v1.0/iMab antibody-10E8v1.0-HC-Knob (SEQ ID NO: 30): EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V1.1/iMab抗體 界定10E8v1.1/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8v1.1/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8v1.1/iMab抗體之源自10E8v1.1的輕鏈的胺基酸序列– 10E8v1.1-LC（SEQ ID NO:31）： ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8v1.1/iMab抗體之源自10E8v1.1的重鏈的胺基酸序列- 10E8v1.1 HC-Knob（SEQ ID NO:32）： EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKYYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V1.1/iMab antibody The amino acid sequence MV1-VLCH1 (SEQ ID NO:1) of the light chain derived from MV1 that defines the 10E8v1.1/iMab antibody: DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8v1.1/iMab antibody: QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from 10E8v1.1 that defines the 10E8v1.1/iMab antibody-10E8v1.1-LC (SEQ ID NO: 31): ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGQSYSETTVAPTVSTVHRGSKSYSTEVKANKSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPD The amino acid sequence of the heavy chain derived from 10E8v1.1 defining the 10E8v1.1/iMab antibody-10E8v1.1 HC-Knob (SEQ ID NO: 32): EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKYYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V2.0/iMab抗體（亦稱為10E8.2/iMab抗體） 界定10E8v2.0/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8v2.0/iMab抗體MV1之源自MV1的重鏈的胺基酸序列-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8v2.0/iMab抗體之源自10E8v2.0的輕鏈的胺基酸序列– 10E8v2.0-LC（SEQ ID NO:33）： ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8v2.0/iMab抗體之源自10E8v2.0的重鏈的胺基酸序列- 10E8v2.0-HC-Knob（SEQ ID NO:34）： EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V2.0/iMab antibody (also known as 10E8.2/iMab antibody) The amino acid sequence MV1-VLCH1 (SEQ ID NO:1) of the light chain derived from MV1 that defines the 10E8v2.0/iMab antibody: DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence of the heavy chain derived from MV1 defining the 10E8v2.0/iMab antibody MV1-HC-Hole-Cross (SEQ ID NO: 2): QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8v2.0-derived light chain of the 10E8v2.0/iMab antibody-10E8v2.0-LC (SEQ ID NO: 33): ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8v2.0 defining the 10E8v2.0/iMab antibody-10E8v2.0-HC-Knob (SEQ ID NO: 34): EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V3.0/iMab抗體 界定10E8v3.0/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO:1）： DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8v3.0/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO:2）： QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8v3.0/iMab抗體之源自10E8v3.0的輕鏈的胺基酸序列– 10E8v3.0-LC（SEQ ID NO:15）： SELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGIHDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8v3.0/iMab抗體之源自10E8v3.0的重鏈的胺基酸序列- 10E8v3.0-HC-Knob（SEQ ID NO:16）： EVQLVESGGDLVKPGGSLRLSCSASGFSFKNTWMTWVRQAPGKGLEWVGRITGPGEGWTSDYAATVQGRFTISRNNMIDMLYLEMNRLRTDDTGLYYCVHTEKYYNFWGGYPPGEEYFQHWGRGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V3.0/iMab antibody The amino acid sequence MV1-VLCH1 (SEQ ID NO:1) of the light chain derived from MV1 that defines the 10E8v3.0/iMab antibody: DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8v3.0/iMab antibody: QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from 10E8v3.0 that defines the 10E8v3.0/iMab antibody-10E8v3.0-LC (SEQ ID NO: 15): SELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGIHDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKQSNTECSYSTVSYSTVS The amino acid sequence of the heavy chain derived from 10E8v3.0 defining the 10E8v3.0/iMab antibody-10E8v3.0-HC-Knob (SEQ ID NO: 16): EVQLVESGGDLVKPGGSLRLSCSASGFSFKNTWMTWVRQAPGKGLEWVGRITGPGEGWTSDYAATVQGRFTISRNNMIDMLYLEMNRLRTDDTGLYYCVHTEKYYNFWGGYPPGEEYFQHWGRGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V1.0/P140（H6L10/PRO140）抗體 界定10E8V1.0/P140抗體之源自PRO140的輕鏈的胺基酸序列- PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8V1.0/P140抗體之源自PRO140的重鏈的胺基酸序列- PRO140-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8V1.0/P140抗體之源自L10的輕鏈的胺基酸序列– L10-LC（SEQ ID NO:29）： ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8V1.0/P140抗體之源自H6的重鏈的胺基酸序列– H6-HC-Knob（SEQ ID NO:30）： EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V1.0/P140 (H6L10/PRO140) antibody The amino acid sequence of the PRO140-derived light chain defining the 10E8V1.0/P140 antibody-PRO140-VLCH1 (SEQ ID NO: 11): DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence of the PRO140-derived heavy chain defining the 10E8V1.0/P140 antibody-PRO140-Hole-Cross (SEQ ID NO: 12): EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from L10 that defines the 10E8V1.0/P140 antibody-L10-LC (SEQ ID NO: 29): ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGQSYSETTVAPTVSTVHRGSKSYSTEVKANKSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPD The amino acid sequence of the H6-derived heavy chain that defines the 10E8V1.0/P140 antibody-H6-HC-Knob (SEQ ID NO: 30): EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V1.1/P140抗體 界定10E8V1.1/P140抗體之源自PRO140的輕鏈的胺基酸序列PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8V1.1/P140抗體之源自P140的重鏈的胺基酸序列PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8V1.1/P140抗體之源自10E8v1.1的輕鏈的胺基酸序列– 10E8v1.1-LC（SEQ ID NO:31）： ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8V1.1/P140抗體之源自10E8v1.1的重鏈的胺基酸序列- 10E8v1.1 HC-Knob（SEQ ID NO:32）： EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKYYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V1.1/P140 antibody The amino acid sequence PRO140-VLCH1 (SEQ ID NO: 11) of the light chain derived from PRO140 that defines the 10E8V1.1/P140 antibody: DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence PRO140-HC-Hole-Cross (SEQ ID NO: 12) of the heavy chain derived from P140 that defines the 10E8V1.1/P140 antibody: EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from 10E8v1.1 that defines the 10E8V1.1/P140 antibody-10E8v1.1-LC (SEQ ID NO: 31): ASELTQDPAVSVALKQTVTITCRGDSLRSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPDRFSGSSSGNTASLTIAGAQAEDDADYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGQSYSETTVAPTVSTVHRGSKSYSTEVKANKSHYVSWYQKKPGQAPVLVFYGKNNRPSGIPD The amino acid sequence of the heavy chain derived from 10E8v1.1 defining the 10E8V1.1/P140 antibody-10E8v1.1 HC-Knob (SEQ ID NO: 32): EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKYYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V2.0/P140抗體 界定10E8V2.0/P140抗體之源自PRO140的輕鏈的胺基酸序列PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8V2.0/P140抗體之源自P140的重鏈的胺基酸序列PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8V2.0/P140抗體之源自10E8v2.0的輕鏈的胺基酸序列– 10E8v2.0-LC（SEQ ID NO:33）： ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8V2.0/P140抗體之源自10E8v2.0的重鏈的胺基酸序列- 10E8v2.0 HC-Knob（SEQ ID NO:34）： EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V2.0/P140 antibody The amino acid sequence PRO140-VLCH1 (SEQ ID NO: 11) of the light chain derived from PRO140 that defines the 10E8V2.0/P140 antibody: DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence PRO140-HC-Hole-Cross (SEQ ID NO: 12) of the heavy chain derived from P140 that defines the 10E8V2.0/P140 antibody: EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8v2.0-derived light chain of the 10E8V2.0/P140 antibody-10E8v2.0-LC (SEQ ID NO: 33): ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8v2.0 defining the 10E8V2.0/P140 antibody-10E8v2.0 HC-Knob (SEQ ID NO: 34): EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8V3.0/P140抗體 界定10E8V3.0/P140抗體之源自PRO140的輕鏈的胺基酸序列PRO140-VLCH1（SEQ ID NO:11）： DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8V3.0/P140抗體之源自P140的重鏈的胺基酸序列PRO140-HC-Hole-Cross（SEQ ID NO:12）： EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8V3.0/P140抗體之源自10E8v3.0的輕鏈的胺基酸序列– 10E8v3.0-LC（SEQ ID NO:15）： SELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGIHDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8V3.0/P140抗體之源自10E8v3.0的重鏈的胺基酸序列- 10E8v3.0 HC-Knob（SEQ ID NO:16）： EVQLVESGGDLVKPGGSLRLSCSASGFSFKNTWMTWVRQAPGKGLEWVGRITGPGEGWTSDYAATVQGRFTISRNNMIDMLYLEMNRLRTDDTGLYYCVHTEKYYNFWGGYPPGEEYFQHWGRGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8V3.0/P140 antibody The amino acid sequence PRO140-VLCH1 (SEQ ID NO: 11) of the light chain derived from PRO140 that defines the 10E8V3.0/P140 antibody: DIVMTQSPLSLPVTPGEPASISCRSSQRLLSSYGHTYLHWYLQKPGQSPQLLIYEVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGQGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALGCLVKDKKVESCVKVSCVKKVHTVHTVSCVK The amino acid sequence PRO140-HC-Hole-Cross (SEQ ID NO: 12) of the heavy chain derived from P140 that defines the 10E8V3.0/P140 antibody: EVQLVESGGGLVKPGGSLRLSCAASGYTFSNYWIGWVRQAPGKGLEWIGDIYPGGNYIRNNEKFKDKTTLSADTSKNTAYLQMNSLKTEDTAVYYCGSSFGSNYVFAWFTYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK The amino acid sequence of the light chain derived from 10E8v3.0 that defines the 10E8V3.0/P140 antibody-10E8v3.0-LC (SEQ ID NO: 15): SELTQETGVSVALGRTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGIHDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSYLTVPEGVASTPSKQSNTECSYSTVSYSTVS The amino acid sequence of the heavy chain derived from 10E8v3.0 defining the 10E8V3.0/P140 antibody-10E8v3.0 HC-Knob (SEQ ID NO: 16): EVQLVESGGDLVKPGGSLRLSCSASGFSFKNTWMTWVRQAPGKGLEWVGRITGPGEGWTSDYAATVQGRFTISRNNMIDMLYLEMNRLRTDDTGLYYCVHTEKYYNFWGGYPPGEEYFQHWGRGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.1/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.1/iMab抗體之源自10E8.2.1的重鏈的胺基酸序列- 10E8.2.1-HC-Knob（SEQ ID NO:35） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNTKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.1/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.1 that defines the 10E8.2.1/iMab antibody-10E8.2.1-HC-Knob (SEQ ID NO: 35) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNTKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTLVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.2/iMab 界定10E8.2/iMAB抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMAB抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMAB抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.2/iMab抗體之源自10E8.2.2的重鏈的胺基酸序列- 10E8.2.2-HC-Knob（SEQ ID NO:36） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.2/iMab The amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 that defines the 10E8.2/iMAB antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMAB antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMAB antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.2 defining the 10E8.2.2/iMab antibody-10E8.2.2-HC-Knob (SEQ ID NO: 36) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRLNSINFLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.3/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.3/iMab抗體之源自10E8.2.3的重鏈的胺基酸序列- 10E8.2.3-HC-Knob（SEQ ID NO:37） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNTKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.3/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.3 that defines the 10E8.2.3/iMab antibody-10E8.2.3-HC-Knob (SEQ ID NO: 37) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNTKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.4/iMab 界定10E8.2.4/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1-LM52（SEQ ID NO:38） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWANSTESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.3/iMab抗體之源自10E8.2.3的重鏈的胺基酸序列- 10E8.2.3-HC-Knob（SEQ ID NO:39） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNTKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.4/iMab The amino acid sequence MV1-VLCH1-LM52 (SEQ ID NO:38) of the light chain derived from MV1 that defines the 10E8.2.4/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWANSTESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAPSGTVKKVLVQSPEPVTVSWNSGALTSGVHTVQVQSLVKVHTVQVPSKVK The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.3 defining the 10E8.2.3/iMab antibody-10E8.2.3-HC-Knob (SEQ ID NO: 39) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNTKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.5/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.5 /iMab抗體之源自10E8.2.5的重鏈的胺基酸序列- 10E8.2.5 -HC-Knob（SEQ ID NO:40） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRKNSINTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.5/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.5 defining the 10E8.2.5/iMab antibody-10E8.2.5 -HC-Knob (SEQ ID NO: 40) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRKNSINTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.6/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.6/iMab抗體之源自10E8.2.6的重鏈的胺基酸序列- 10E8.2.6-HC-Knob（SEQ ID NO:41） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNSINTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.6/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.6 defining the 10E8.2.6/iMab antibody-10E8.2.6-HC-Knob (SEQ ID NO: 41) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNSINTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.7/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.4/iMab抗體之源自10E8.4的重鏈的胺基酸序列- 10E8.4-HC-Knob（SEQ ID NO:42） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRKNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.7/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV Defines the amino acid sequence of the 10E8.4-derived heavy chain of the 10E8.4/iMab antibody-10E8.4-HC-Knob (SEQ ID NO: 42) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRKNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.8/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.2/iMab抗體之源自10E8.2的輕鏈的胺基酸序列– 10E8.2-LC（SEQ ID NO: 33） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.8/iMab抗體之源自10E8.2.8的重鏈的胺基酸序列- 10E8.2.8-HC-Knob（SEQ ID NO:43） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.8/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.2-derived light chain of the 10E8.2/iMab antibody-10E8.2-LC (SEQ ID NO: 33) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKPGQAPILLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVPEGVTPSKGSSYSTVTSVPEQYPGAVTVAWASSYLTVPEGVTPSKSYSTVSTV The amino acid sequence of the heavy chain derived from 10E8.2.8 defining the 10E8.2.8/iMab antibody-10E8.2.8-HC-Knob (SEQ ID NO: 43) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.2.10/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.4/iMab抗體之源自10E8.4的輕鏈的胺基酸序列– 10E8.4-LC（SEQ ID NO:44） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKTGQAPKLLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.2.8/iMab抗體之源自10E8.2.8的重鏈的胺基酸序列- 10E8.2.8-HC-Knob（SEQ ID NO:45） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.2.10/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.4-derived light chain of the 10E8.4/iMab antibody-10E8.4-LC (SEQ ID NO: 44) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKTGQAPKLLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKTGQAPKLLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWASSYLSSPVPEGVTPSKGSSYSTVTSTVTSVPEQYPGAVTSQTSV The amino acid sequence of the heavy chain derived from 10E8.2.8 defining the 10E8.2.8/iMab antibody-10E8.2.8-HC-Knob (SEQ ID NO: 45) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRDNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

10E8.4/iMab 界定10E8.2/iMab抗體之源自MV1的輕鏈的胺基酸序列MV1-VLCH1（SEQ ID NO: 1） DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 界定10E8.2/iMab抗體之源自MV1的重鏈的胺基酸序列MV1-HC-Hole-Cross（SEQ ID NO: 2） QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK 界定10E8.4/iMab抗體之源自10E8.4的輕鏈的胺基酸序列– 10E8.4-LC（SEQ ID NO:46） ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKTGQAPKLLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 界定10E8.4/iMab抗體之源自10E8.4的重鏈的胺基酸序列- 10E8.4-HC-Knob（SEQ ID NO:47） EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRKNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK10E8.4/iMab Defines the amino acid sequence MV1-VLCH1 (SEQ ID NO: 1) of the light chain derived from MV1 of the 10E8.2/iMab antibody DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTICLVKDYFPEPVTVSLTYVQVHTVHTKKVNHPSGVNHPSKN The amino acid sequence MV1-HC-Hole-Cross (SEQ ID NO: 2) of the heavy chain derived from MV1 that defines the 10E8.2/iMab antibody QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSASTAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Defines the amino acid sequence of the 10E8.4-derived light chain of the 10E8.4/iMab antibody-10E8.4-LC (SEQ ID NO: 46) ASELTQDPAVSVALKQTVTITCRGDSLRSHYASWYQKKTGQAPKLLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQTVTITCRGDSLRSHYASWYQKKTGQAPKLLFYGKNNRPSGVPDRFSGSASGNRASLTISGAQAEDDAEYYCSSRDKSGSRLSVFGGGTKLTVLSQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWASSYLSSPVPEGVTPSKGSSYSTVTSTVTSVPEQYPGAVTSQTSV Defines the amino acid sequence of the 10E8.4-derived heavy chain of the 10E8.4/iMab antibody-10E8.4-HC-Knob (SEQ ID NO: 47) EVRLVESGGGLVKPGGSLRLSCSASGFNFDDAWMTWVRQPPGKGLEWVGRISGPGEGWSVDYAESVKGRFTISRKNSKNTLYLEMNNVRTEDTGYYFCARTGKHYDFWSGYPPGEEYFQDWGQGTKVIVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK

於各種實施方式中，得自PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、10E8、P140、iMab（或其MV1變體）、515H7抗體及其等之變體的重鏈及／或輕鏈序列之至少一者係彼此配對以形成雙專一性抗體（例如HIV CrossMab抗體）。於例示性實施方式中，選自SEQ ID NO: 1-36的所揭示的重鏈及輕鏈之至少一者係彼此配對以形成雙專一性抗體（例如HIV CrossMab抗體）。In various embodiments, derived from PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, 10E8, P140, iMab (or its MV1 variant), 515H7 antibody and variants thereof At least one of the heavy chain and/or light chain sequences is paired with each other to form a bispecific antibody (for example, the HIV CrossMab antibody). In an exemplary embodiment, at least one of the heavy and light chains disclosed in SEQ ID NOs: 1-36 is paired with each other to form a bispecific antibody (eg, HIV CrossMab antibody).

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）之胺基酸序列進一步包括胺基酸類似物、胺基酸衍生物、或其他非典型胺基酸。In various embodiments, the amino acid sequence of the bispecific antibody (such as the HIV CrossMab antibody) further includes amino acid analogs, amino acid derivatives, or other atypical amino acids.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含與PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、或10E8抗體之野生型重鏈或輕鏈序列至少60%一致的序列。於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含與P140、iMab（或其MV1變體）、或515H7抗體之野生型重鏈或輕鏈序列至少60%一致的序列。於例示性實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含與於本文中揭示的序列之任何者至少60%一致的序列。In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) comprises the wild-type heavy chain or light chain of the antibody to PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, or 10E8. The sequence is at least 60% identical. In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) comprises a sequence that is at least 60% identical to the wild-type heavy chain or light chain sequence of the P140, iMab (or its MV1 variant), or 515H7 antibody. In an exemplary embodiment, the bispecific antibody (eg, HIV CrossMab antibody) comprises a sequence that is at least 60% identical to any of the sequences disclosed herein.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）可包含與PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、或10E8抗體之野生型重鏈或輕鏈序列至少約60%、至少約61%、至少約62%、至少約63%、至少約64%、至少約65%、至少約66%、至少約67%、至少約68%、至少約69%、至少約70%、至少約71%、至少約72%、至少約73%、至少約74%、至少約75%、至少約76%、至少約77%、至少約78%、至少約79%、至少約80%、至少約81%、至少約82%、至少約83%、至少約84%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%、或100%一致的序列。In various embodiments, the bispecific antibody (e.g., HIV CrossMab antibody) may comprise a wild-type heavy chain or light-type antibody with PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, or 10E8 antibody. The chain sequence is at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69 %, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79 %, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89 %, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99 %, or 100% identical sequence.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）可包含與P140、iMab（或其MV1變體）、或515H7抗體之野生型重鏈或輕鏈序列至少約60%、至少約61%、至少約62%、至少約63%、至少約64%、至少約65%、至少約66%、至少約67%、至少約68%、至少約69%、至少約70%、至少約71%、至少約72%、至少約73%、至少約74%、至少約75%、至少約76%、至少約77%、至少約78%、至少約79%、至少約80%、至少約81%、至少約82%、至少約83%、至少約84%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%、或100%一致的序列。In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) may comprise at least about 60%, at least about the wild-type heavy chain or light chain sequence of the P140, iMab (or its MV1 variant), or 515H7 antibody. 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical sequences.

於例示性實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）可包含與於本文中揭示的序列之任何者至少約60%、至少約61%、至少約62%、至少約63%、至少約64%、至少約65%、至少約66%、至少約67%、至少約68%、至少約69%、至少約70%、至少約71%、至少約72%、至少約73%、至少約74%、至少約75%、至少約76%、至少約77%、至少約78%、至少約79%、至少約80%、至少約81%、至少約82%、至少約83%、至少約84%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%、或100%一致的序列。In an exemplary embodiment, the bispecific antibody (e.g., HIV CrossMab antibody) may comprise at least about 60%, at least about 61%, at least about 62%, at least about 63%, and any sequence disclosed herein. At least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, At least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, At least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, A sequence that is at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical.

同一性（homology）或一致性（identity）可以在所屬技術領域中的技術內各種方式測定，該等方式例如為使用公眾可得的電腦軟體，諸如BLAST、BLAST-2、ALIGN或Megalign（DNASTAR）軟體。使用程式blastp、blastn、blastx、tblastn及tblastx（Karlin等人, (1990) Proc. Natl. Acad. Sci. USA 87, 2264-2268；Altschul, (1993) J. Mol. Evol. 36, 290-300；Altschul等人, (1997) Nucleic Acids Res. 25, 3389-3402，其等以引用方式併入）利用的演算法的BLAST（基礎局部排比搜尋工具，Basic Local Alignment Search Tool）分析係針對序列類似性搜尋特別製作。BLAST程式使用的方法係首先考慮在問題序列及資料庫序列間類似的節段，接著評估所有鑑認出的匹配之統計顯著性及最後總結單單該等滿足顯著性之預選閾值的匹配。對於序列資料庫之類似性搜尋中的基本議題之討論，參見Altschul等人, (1994) Nature Genetics 6, 119-129，其以引用方式完整併入。所屬技術領域中具有通常知識者可決定測量排比用的適當參數，包括達成覆蓋所比較的序列之全長的最大排比所需的任何演算法。對於直方圖、描述、排比、預期（即對於報告相對於資料庫序列的匹配的統計顯著性閾值）、截止、矩陣及篩選器的搜尋參數係於預設設定。blastp、blastx、tblastn、及tblastx所使用的預設評分矩陣係BLOSUM62矩陣（Henikoff等人, (1992) Proc. Natl. Acad. Sci. USA 89, 10915-10919，其以引用方式完整併入）。四個blastn參數可如下調整：Q=10（空位生成罰分）；R=10（空位擴展罰分）；wink=1（於沿著問題序列的每個wink.sup.th位置產生字吻合）；及gapw=16（設定加空位的排比於其中產生的窗寬）。相等的Blastp參數設定可為Q=9；R=2；wink=1；及gapw=32。搜尋可亦使用NCBI（國家生物技術資訊中心，National Center for Biotechnology Information）BLAST進階選擇參數（BLAST Advanced Option Parameter）進行（例如：-G，打開空位之代價[整數]：對於核苷酸預設= 5 / 對於蛋白質預設= 11；-E，擴展空位之代價[整數]：對於核苷酸預設= 2/對於蛋白質預設= 1；-q，對於核苷酸錯配的罰分[整數]：預設= -3；-r，對於核苷酸匹配的得分[整數]：預設= 1；-e，預期值[實際]：預設= 10；-W，字長[整數]：對於核苷酸預設= 11/對於megablast預設= 28/對於蛋白質預設= 3；-y，以位元計的對於blast擴展的停止（Dropoff）（X）：對於blastn預設= 20 /對於其他預設= 7；-X，對於加空位的排比的X停止值（以位元計）：對於所有程式預設= 15，但不適用於blastn；及–Z，對於加空位的排比的最終X停止值（以位元計）：對於blastn為50，對於其他者為25）。亦可使用用於逐對蛋白質排比的ClustalW（預設參數可包括（例如）Blosum62矩陣及空位打開罰分= 10及空位擴展罰分= 0.1）。序列間的Bestfit比較（可於GCG套裝版本10.0中獲得）使用DNA參數GAP=50（空位生成罰分）及LEN=3（空位擴展罰分）且於蛋白質比較的相等設定係GAP=8及LEN=2。Homology or identity can be determined in various ways within the technology in the technical field, such as the use of publicly available computer software, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Use programs blastp, blastn, blastx, tblastn and tblastx (Karlin et al., (1990) Proc. Natl. Acad. Sci. USA 87, 2264-2268; Altschul, (1993) J. Mol. Evol. 36, 290-300 ; Altschul et al., (1997) Nucleic Acids Res. 25, 3389-3402, which are incorporated by reference) BLAST (Basic Local Alignment Search Tool) analysis of the algorithm used for sequence similarity Sex search is specially made. The method used by the BLAST program first considers the similar segments between the question sequence and the database sequence, then evaluates the statistical significance of all identified matches and finally summarizes only those matches that meet the preselected threshold of significance. For a discussion of basic issues in the similarity search of sequence databases, see Altschul et al., (1994) Nature Genetics 6, 119-129, which is fully incorporated by reference. Those skilled in the art can determine the appropriate parameters for measuring alignment, including any algorithm required to achieve the maximum alignment covering the full length of the sequence being compared. The search parameters for histogram, description, alignment, expectation (that is, the statistical significance threshold for the match of the report with respect to the database sequence), cutoff, matrix and filter are set by default. The default scoring matrix used by blastp, blastx, tblastn, and tblastx is the BLOSUM62 matrix (Henikoff et al., (1992) Proc. Natl. Acad. Sci. USA 89, 10915-10919, which is fully incorporated by reference). The four blastn parameters can be adjusted as follows: Q=10 (gap generation penalty); R=10 (gap expansion penalty); wink=1 (a word coincidence is generated at each wink.sup.th position along the problem sequence) ; And gapw=16 (set the width of the window generated by the row ratio of the space added). The equivalent Blastp parameter settings can be Q=9; R=2; wink=1; and gapw=32. The search can also be performed using NCBI (National Center for Biotechnology Information) BLAST Advanced Option Parameter (for example: -G, the cost of opening the gap [integer]: preset for nucleotides = 5 / Preset for protein = 11; -E, the cost of expanding gaps [integer]: Preset for nucleotides = 2/ Preset for proteins = 1; -q, penalty for nucleotide mismatches [ Integer]: default = -3; -r, score for nucleotide matching [integer]: default = 1; -e, expected value [actual]: default = 10; -W, word length [integer] : Preset for nucleotides = 11/ Preset for megablast = 28/ Preset for proteins = 3; -y, stop for blast expansion in bits (Dropoff) (X): Preset for blastn = 20 /For other presets = 7; -X, X stop value (in bits) for parallels with gaps: default = 15 for all programs, but not applicable to blastn; and -Z, for parallels with gaps The final X stop value of (in bits): 50 for blastn, 25 for others). ClustalW for pair-wise protein alignment can also be used (preset parameters can include, for example, Blosum62 matrix and gap opening penalty = 10 and gap expansion penalty = 0.1). Bestfit comparison between sequences (available in GCG package version 10.0) uses DNA parameters GAP=50 (gap generation penalty) and LEN=3 (gap expansion penalty), and the equal settings for protein comparison are GAP=8 and LEN = 2.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含包括至少一個關於PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、或10E8抗體之野生型重鏈或輕鏈序列的胺基酸改變的序列。於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含包括至少一個關於P140、iMab（或其MV1變體）、515H7抗體之野生型重鏈或輕鏈序列的胺基酸改變的序列。於例示性實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含包括至少一個關於於本文中揭示的序列之任何者的胺基酸改變的序列。In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) comprises at least one wild-type heavy chain related to PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, or 10E8 antibody Or a sequence in which the amino acid of the light chain sequence is changed. In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) comprises at least one amino acid change related to the wild-type heavy chain or light chain sequence of the P140, iMab (or its MV1 variant), and 515H7 antibody. sequence. In an exemplary embodiment, the bispecific antibody (eg, HIV CrossMab antibody) comprises a sequence that includes at least one amino acid change with respect to any of the sequences disclosed herein.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含包括至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、40、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、或80個關於PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、或10E8抗體之野生型重鏈或輕鏈序列的胺基酸改變的序列。In various embodiments, the bispecific antibody (for example, HIV CrossMab antibody) comprises at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 40, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 , 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 about PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151 , 4E10, or 10E8 antibody wild-type heavy chain or light chain sequence with amino acid changes.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含包括至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、40、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、或80個關於P140、iMab（或其MV1變體）、或515H7抗體之野生型重鏈或輕鏈序列的胺基酸改變的序列。In various embodiments, the bispecific antibody (for example, HIV CrossMab antibody) comprises at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 40, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 , 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 wild type related to P140, iMab (or its MV1 variant), or 515H7 antibody A sequence in which the amino acid of the heavy chain or light chain sequence is changed.

於例示性實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）包含包括至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、40、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、或80個關於於本文中揭示的序列之任何者的胺基酸改變的序列。In an exemplary embodiment, the bispecific antibody (such as the HIV CrossMab antibody) includes at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 40, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 sequences with amino acid changes in any of the sequences disclosed herein .

該胺基酸改變可係胺基酸缺失、插入、取代、或修改。於一個實施方式中，該胺基酸改變係胺基酸缺失。於另一個實施方式中，該胺基酸改變係胺基酸取代。The amino acid change can be a deletion, insertion, substitution, or modification of an amino acid. In one embodiment, the amino acid change is an amino acid deletion. In another embodiment, the amino acid change is an amino acid substitution.

於各種實施方式中，該胺基酸改變可位於該雙專一性抗體之互補性決定區（CDR）（例如其CDR1、CDR2或CDR3區）中。於另一個實施方式中，該胺基酸改變可位於該雙專一性抗體之骨架區（FW）（例如其FW1、FW2、FW3、或FW4區）中。於進一步的實施方式中，該胺基酸改變可位於該雙專一性抗體之連接區（J區）（例如其之J1、J2、J3、J4、J5、J6、或J7區）中。In various embodiments, the amino acid change can be located in the complementarity determining region (CDR) of the bispecific antibody (for example, its CDR1, CDR2, or CDR3 region). In another embodiment, the amino acid change may be located in the framework region (FW) of the bispecific antibody (for example, its FW1, FW2, FW3, or FW4 region). In a further embodiment, the amino acid change may be located in the linking region (J region) of the bispecific antibody (for example, the J1, J2, J3, J4, J5, J6, or J7 region) of the bispecific antibody.

亦於本文中提供者係該等雙專一性抗體之嵌合抗體衍生物，即以下抗體分子以及如此抗體之片段（只要其等展現所欲的生物活性即可）：其中其重鏈及／或輕鏈之部分與得自特定物種或屬於特定抗體類型或亞型的抗體中的相對應序列完全相同或同源，而鏈的剩下部分與得自另一物種或屬於另一個抗體類型或亞型的抗體中的相對應序列完全相同或同源。例如，該雙專一性抗體可包括以下重鏈及／或輕鏈：其中一或多個得自選自PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、10E8、P140、iMab（或其MV1變體）、或515H7抗體的抗體之CDR或FW係以一或多個得自選自PGT145、PG9、PGT128、PGT121、10-1074、3BNC117、VRC01、PGT151、4E10、10E8、P140、iMab（或其MV1變體）、或515H7抗體的不同抗體之CDR或FW置換。Also provided herein are the chimeric antibody derivatives of these bispecific antibodies, that is, the following antibody molecules and fragments of such antibodies (as long as they exhibit the desired biological activity): wherein its heavy chain and/or A part of the light chain is completely identical or homologous to the corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody type or subtype, while the remaining part of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody type or subtype. The corresponding sequences in the type of antibody are completely identical or homologous. For example, the bispecific antibody may include the following heavy chains and/or light chains: one or more of them are selected from PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, 10E8, P140, The CDR or FW of the iMab (or its MV1 variant) or the antibody of the 515H7 antibody is derived from one or more selected from PGT145, PG9, PGT128, PGT121, 10-1074, 3BNC117, VRC01, PGT151, 4E10, 10E8, P140 , IMab (or its MV1 variant), or CDR or FW substitution of a different antibody of the 515H7 antibody.

於各種實施方式中，本發明提供展現與溶解度、穩定性、及治療活性有關的有利特性的改良的雙專一性抗體。設想到如此抗體可特別適用於大規模商業製造。例如，如此抗體可在製造期間展現增加的溶解度、減少的聚集、減少的沈澱、及／或增強的穩定性或對降解的抗性。In various embodiments, the present invention provides improved bispecific antibodies that exhibit advantageous properties related to solubility, stability, and therapeutic activity. It is envisaged that such antibodies may be particularly suitable for large-scale commercial manufacturing. For example, such antibodies may exhibit increased solubility, decreased aggregation, decreased precipitation, and/or increased stability or resistance to degradation during manufacture.

於例示性實施方式中，該改良的雙專一性抗體係10E8V2.0/iMab抗體（亦稱為10E8.2/iMab抗體）之變體。於如此實施方式中，該變體相較於親本10E8V2.0/iMab抗體可展現增強的溶解度、穩定性、及／或治療活性（例如抗病毒活性）。In an exemplary embodiment, the modified bispecific antibody system 10E8V2.0/iMab antibody (also referred to as a variant of 10E8.2/iMab antibody). In such an embodiment, the variant may exhibit enhanced solubility, stability, and/or therapeutic activity (for example, antiviral activity) compared to the parental 10E8V2.0/iMab antibody.

於一些實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）可包含與10E8V2.0/iMab抗體之重鏈或輕鏈序列（即SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO: 33、或SEQ ID NO:34）至少約60%、至少約61%、至少約62%、至少約63%、至少約64%、至少約65%、至少約66%、至少約67%、至少約68%、至少約69%、至少約70%、至少約71%、至少約72%、至少約73%、至少約74%、至少約75%、至少約76%、至少約77%、至少約78%、至少約79%、至少約80%、至少約81%、至少約82%、至少約83%、至少約84%、至少約85%、至少約86%、至少約87%、至少約88%、至少約89%、至少約90%、至少約91%、至少約92%、至少約93%、至少約94%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%、或100%一致的序列。In some embodiments, the bispecific antibody (such as the HIV CrossMab antibody) may comprise the heavy chain or light chain sequence of the 10E8V2.0/iMab antibody (ie SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO : 33, or SEQ ID NO: 34) at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, At least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, At least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, At least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, A sequence that is at least about 98%, at least about 99%, or 100% identical.

於各種實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）可包含包括至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、40、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、或80個關於10E8V2.0/iMab抗體（即SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO: 33、或SEQ ID NO:34）之重鏈或輕鏈序列的胺基酸改變的序列。In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) may include at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 40, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 related to 10E8V2.0/iMab antibody (ie SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:33, or SEQ ID NO:34) the sequence of the amino acid change of the heavy chain or light chain sequence.

於各種實施方式中，該雙專一性抗體可包含一或多個位於10E8V2.0/iMab抗體之互補性決定區（CDR）（例如其CDR1、CDR2或CDR3區）的胺基酸改變。於另一個實施方式中，該雙專一性抗體可包含一或多個位於該雙專一性抗體之骨架區（FW）（例如the FW1、FW2、FW3、或FW4區）的胺基酸改變。於進一步的實施方式中，該胺基酸改變可位於10E8V2.0/iMab抗體之連接區（J區）（例如J1、J2、J3、J4、J5、J6、或J7區）。In various embodiments, the bispecific antibody may include one or more amino acid changes located in the complementarity determining region (CDR) of the 10E8V2.0/iMab antibody (for example, its CDR1, CDR2, or CDR3 region). In another embodiment, the bispecific antibody may comprise one or more amino acid changes located in the framework region (FW) of the bispecific antibody (for example, the FW1, FW2, FW3, or FW4 region). In a further embodiment, the amino acid change may be located in the junction region (J region) of the 10E8V2.0/iMab antibody (for example, J1, J2, J3, J4, J5, J6, or J7 region).

於一些實施方式中，該雙專一性抗體包含得自10E8V2.0的變體重鏈（即SEQ ID NO:34）。於如此實施方式中，該雙專一性抗體可包括一或多個位於選自重鏈之L72、I75、F77、L89、Y98、F100a、W100b、Y100e、P100f、P100g、L108、及／或L170的位置的突變（在SEQ ID NO: 34上的突變位置係由Kabat編號系統決定）。於一些實施方式中，該雙專一性抗體可包括一或多個位於選自L72、I75、F77、及／或L108的位置的突變。於一些實施方式中，該雙專一性抗體可包括該一或多個選自L72K、I75K、F77T、及L108K的突變。於一個實施方式中，該雙專一性抗體包含包含SEQ ID NO: 47之胺基酸序列的重鏈。In some embodiments, the bispecific antibody comprises a variant weight chain derived from 10E8V2.0 (ie SEQ ID NO: 34). In such an embodiment, the bispecific antibody may include one or more positions selected from L72, I75, F77, L89, Y98, F100a, W100b, Y100e, P100f, P100g, L108, and/or L170 of the heavy chain (The position of the mutation in SEQ ID NO: 34 is determined by the Kabat numbering system). In some embodiments, the bispecific antibody may include one or more mutations at positions selected from L72, I75, F77, and/or L108. In some embodiments, the bispecific antibody may include the one or more mutations selected from L72K, I75K, F77T, and L108K. In one embodiment, the bispecific antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 47.

於一些實施方式中，該雙專一性抗體包含得自10E8V2.0（即SEQ ID NO:33）的變體輕鏈。於如此實施方式中，該雙專一性抗體可包括一或多個選自該輕鏈之L15、P40、I45、及P112的位置的突變（位於SEQ ID NO: 33的突變位置係由Kabat編號系統決定）。於一些實施方式中，該雙專一性抗體可包括一或多個位於選自P40及I45的位置的突變。於一些實施方式中，該雙專一性抗體可包括一或多個選自P40T及I45K的突變。於一個實施方式中，該雙專一性抗體包含包含SEQ ID NO: 46之胺基酸序列的輕鏈。In some embodiments, the bispecific antibody comprises a variant light chain derived from 10E8V2.0 (ie SEQ ID NO: 33). In such an embodiment, the bispecific antibody may include one or more mutations selected from the positions of L15, P40, I45, and P112 of the light chain (the mutation positions in SEQ ID NO: 33 are determined by the Kabat numbering system Decide). In some embodiments, the bispecific antibody may include one or more mutations at positions selected from P40 and I45. In some embodiments, the bispecific antibody may include one or more mutations selected from P40T and I45K. In one embodiment, the bispecific antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 46.

於一些實施方式中，該雙專一性抗體包含得自MV1的變體輕鏈（即SEQ ID NO: 1）。於如此實施方式中，該雙專一性抗體可包括位於位置52-54的突變（在SEQ ID NO: 1上的突變位置係由Kabat編號系統決定）。於一些實施方式中，該雙專一性抗體可包括位於位置52-54的胺基酸突變。於一些實施方式中，位於位置52的胺基酸被突變成Asn（N），位於位置53的胺基酸被突變成Ser（S），且位於位置54的胺基酸被突變成Thr（T）。於一些實施方式中，位於位置52的Asn突變係N-連結性醣苷化的。於一個實施方式中，該雙專一性抗體包含包含SEQ ID NO: 38之胺基酸序列的輕鏈。In some embodiments, the bispecific antibody comprises a variant light chain derived from MV1 (ie SEQ ID NO: 1). In such an embodiment, the bispecific antibody may include mutations at positions 52-54 (the position of the mutation in SEQ ID NO: 1 is determined by the Kabat numbering system). In some embodiments, the bispecific antibody may include amino acid mutations at positions 52-54. In some embodiments, the amino acid at position 52 is mutated to Asn(N), the amino acid at position 53 is mutated to Ser(S), and the amino acid at position 54 is mutated to Thr(T ). In some embodiments, the Asn mutation at position 52 is N-linked glycosylated. In one embodiment, the bispecific antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 38.

於闡明性實施方式中，該雙專一性抗體包含得自10E8且分別包含SEQ ID NO: 47及SEQ ID NO:46之胺基酸序列的重鏈及輕鏈。該雙專一性抗體進一步包含得自MV1且分別包含SEQ ID NO: 1及SEQ ID NO:2之胺基酸序列的重鏈及輕鏈。In an illustrative embodiment, the bispecific antibody comprises a heavy chain and a light chain derived from 10E8 and comprising the amino acid sequences of SEQ ID NO: 47 and SEQ ID NO: 46, respectively. The bispecific antibody further comprises a heavy chain and a light chain derived from MV1 and comprising the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively.

重組結合性蛋白質之胺基酸序列之修改係使用任何所屬技術領域中已知的技術（例如定點誘變或基於PCR的誘變）達成。如此技術係（例如）於Sambrook等人,Molecular Cloning: A Laboratory Manual , Cold Spring Harbor Press, Plainview, N.Y., 1989及Ausubel等人,Current Protocols in Molecular Biology , John Wiley & Sons, New York, N.Y., 1989中描述。The modification of the amino acid sequence of the recombinant binding protein is achieved by using any technique known in the art (such as site-directed mutagenesis or PCR-based mutagenesis). Such techniques are, for example, described in Sambrook et al., Molecular Cloning: A Laboratory Manual , Cold Spring Harbor Press, Plainview, NY, 1989 and Ausubel et al., Current Protocols in Molecular Biology , John Wiley & Sons, New York, NY, 1989 Described in.

用於製造抗體（諸如該等於本文中揭示者）的方法於所屬技術領域中係已知的。例如，編碼輕鏈可變區及／或重鏈可變區的DNA分子可使用於本文中提供的序列資訊化學合成。可將合成性DNA分子連接至其他適當的核苷酸序列（包括（例如）表現控制序列）以製造編碼所欲抗體的習用基因表現構築體。所定義基因構築體之製造係在所屬技術領域中的例行技術內。或者，可將於本文中提供的序列藉由習用雜交技術或聚合酶連鎖反應（PCR）技術使用其序列係基於於本文中提供的序列資訊或有關編碼該重鏈及輕鏈的基因的先前技術序列資訊的合成性核酸探針由融合瘤選殖出。Methods for making antibodies (such as those disclosed herein) are known in the art. For example, DNA molecules encoding the variable region of the light chain and/or the variable region of the heavy chain can be used in the chemical synthesis of the sequence information provided herein. Synthetic DNA molecules can be linked to other appropriate nucleotide sequences (including, for example, expression control sequences) to create conventional gene expression constructs encoding the desired antibody. The manufacturing of the defined gene construct is within the routine technology in the technical field. Alternatively, the sequence provided herein can be used by conventional hybridization technology or polymerase chain reaction (PCR) technology. The sequence is based on the sequence information provided herein or prior art related to the genes encoding the heavy and light chains. Synthetic nucleic acid probes with sequence information are selected and cloned from fusion tumors.

可將編碼所欲抗體的核酸併入（連接）至表現載體內，且可透過習用轉染或轉形技術將該表現載體該導入至宿主細胞中。例示性宿主細胞為大腸桿菌細胞、中國倉鼠卵巢（CHO）細胞、人類胚胎腎臟293（HEK 293）細胞、HeLa細胞、倉鼠嬰腎（BHK）細胞、猴腎臟細胞（COS）、人類肝細胞癌細胞（例如Hep G2）、及骨髓瘤細胞，其等否則不會製造IgG蛋白質。可使經轉形宿主細胞在允許該等宿主細胞表現編碼免疫球蛋白輕鏈及／或重鏈可變區的基因的條件下生長。專一性表現及純化條件會隨所利用的表現系統而改變。The nucleic acid encoding the desired antibody can be incorporated (linked) into the expression vector, and the expression vector can be introduced into the host cell through conventional transfection or transformation techniques. Exemplary host cells are E. coli cells, Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK 293) cells, HeLa cells, hamster infant kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (Such as Hep G2), and myeloma cells, which would otherwise not produce IgG protein. The transformed host cells can be grown under conditions that allow the host cells to express genes encoding immunoglobulin light chain and/or heavy chain variable regions. Specific performance and purification conditions will vary with the performance system used.

於各種實施方式中，本發明之雙專一性抗體（例如HIV CrossMab抗體）係於治療中使用。例如，該雙專一性抗體（例如HIV CrossMab抗體）可用於在哺乳動物（例如人類患者）中中和HIV。例如，本發明之抗體可與HIV結合以部分或完全抑制該病毒之一或多種生物活性。於一個實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）中和R5-向性HIV。於另一個實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）中和X4-向性HIV。於進一步的實施方式中，該雙專一性抗體（例如HIV CrossMab抗體）中和R5X4雙向性HIV。於一些實施方式中，使用該抗體以於哺乳動物中中和HIV包含將治療有效量的該抗體投予至該哺乳動物。In various embodiments, the bispecific antibody (such as the HIV CrossMab antibody) of the present invention is used in therapy. For example, the bispecific antibody (such as the HIV CrossMab antibody) can be used to neutralize HIV in mammals (such as human patients). For example, the antibody of the present invention can bind to HIV to partially or completely inhibit one or more biological activities of the virus. In one embodiment, the bispecific antibody (eg, HIV CrossMab antibody) neutralizes R5-tropic HIV. In another embodiment, the bispecific antibody (such as the HIV CrossMab antibody) neutralizes X4-tropic HIV. In a further embodiment, the bispecific antibody (such as the HIV CrossMab antibody) neutralizes R5X4 bidirectional HIV. In some embodiments, using the antibody to neutralize HIV in a mammal comprises administering a therapeutically effective amount of the antibody to the mammal.

一般而言，活性組份之治療有效量係在例如約0.1 mg/kg至約100 mg/kg，例如約1 mg/kg至約100 mg/kg，例如約1 mg/kg至約10 mg/kg的患者之體重的範圍內。於各種實施方式中，活性組份之治療有效量係在約0.01 mg/kg至約30 mg/kg的患者之體重的範圍內，例如約0.01 mg/kg、約0.02 mg/kg、約0.03 mg/kg、約0.04 mg/kg、約0.05 mg/kg、約0.06 mg/kg、約0.07 mg/kg、約0.08 mg/kg、約0.09 mg/kg、約0.1 mg/kg、約0.2 mg/kg、約0.3 mg/kg、約0.4 mg/kg、約0.5 mg/kg、約0.6 mg/kg、約0.7 mg/kg、約0.8 mg/kg、約0.9 mg/kg、約1 mg/kg、約1.1 mg/kg、約1.2 mg/kg、約1.3 mg/kg、約1.4 mg/kg、約1.5mg/kg、約1.6 mg/kg、約1.7 mg/kg、約1.8 mg/kg、1.9 mg/kg、約2 mg/kg、約3 mg/kg、約4 mg/kg、約5 mg/kg、約6 mg/kg、約7 mg/kg、約8 mg/kg、約9 mg/kg、約10 mg/kg、約11 mg/kg、約12 mg/kg、約13 mg/kg、約14 mg/kg、約15 mg/kg、約16 mg/kg、約17 mg/kg、約18 mg/kg、約19 mg/kg、約20 mg/kg、約21 mg/kg、約22 mg/kg、約23 mg/kg、約24 mg/kg、約25 mg/kg、約26 mg/kg、約27 mg/kg、約28 mg/kg、約29 mg/kg、約30 mg/kg體重，包括其內的所有值及範圍。Generally speaking, the therapeutically effective amount of the active ingredient is, for example, about 0.1 mg/kg to about 100 mg/kg, for example, about 1 mg/kg to about 100 mg/kg, for example, about 1 mg/kg to about 10 mg/kg. Within the range of the patient's weight of kg. In various embodiments, the therapeutically effective amount of the active ingredient is in the range of about 0.01 mg/kg to about 30 mg/kg of the patient's body weight, for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg /kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg , About 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, About 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg body weight, including all values and ranges within them.

於一些實施方式中，活性組份之治療有效量係介於約1至10 mg/kg、介於約10至20 mg/kg間、介於約20至30 mg/kg間、介於約30至40 mg/kg間、介於約40至50 mg/kg間、介於約50至60 mg/kg間、介於約60至70 mg/kg間、介於約70至80 mg/kg間、介於約80至90 mg/kg間、或介於約90至100 mg/kg間的任何值。In some embodiments, the therapeutically effective amount of the active ingredient is between about 1 to 10 mg/kg, between about 10 to 20 mg/kg, between about 20 to 30 mg/kg, and between about 30 mg/kg. Between about 40 mg/kg, between about 40 and 50 mg/kg, between about 50 and 60 mg/kg, between about 60 and 70 mg/kg, between about 70 and 80 mg/kg , Any value between about 80 to 90 mg/kg, or between about 90 to 100 mg/kg.

於一些實施方式中，活性組份之治療有效量係約1 mg/kg、約2 mg/kg、約3 mg/kg、約6 mg/kg、約10 mg/kg、約20 mg/kg、約30 mg/kg、或約60 mg/kg，靜脈內地（IV）遞送。In some embodiments, the therapeutically effective amount of the active ingredient is about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 6 mg/kg, about 10 mg/kg, about 20 mg/kg, About 30 mg/kg, or about 60 mg/kg, delivered intravenously (IV).

於一些實施方式中，活性組份之治療有效量係約2.5 mg/kg、約5 mg/kg、約10 mg/kg、或約20 mg/kg，皮下地（s.c.）或肌內地（i.m）遞送。In some embodiments, the therapeutically effective amount of the active ingredient is about 2.5 mg/kg, about 5 mg/kg, about 10 mg/kg, or about 20 mg/kg, subcutaneously (sc) or intramuscularly (im) deliver.

所投予的量會取決於諸如以下者的變數：欲治療的疾病或適應症之類型及程度、患者之總體健康、抗體之活體內效力、醫藥調配物、及投予之途徑。可使最初劑量增加超過上限水平以快速地達成所欲的血液水平或組織水平。或者，可使最初劑量小於最佳值，並可在治療之過程期間逐漸地增加該劑量。人類劑量可（例如）於經設計以（例如）於0.5 mg/kg至20 mg/kg進行的習用第I期劑量累增研究中優化。給藥頻率可基於諸如投予之途徑、劑量及所治療的疾病的因素變化。例示性給藥頻率係每日超過一次、約每日一次、約一日兩次、約一日三次、約一日四次、約一日五次、約每隔一日、約每隔兩日、約一週一次、約每兩週一次、約每月一次、約每兩個月一次、約每三個月一次、約每六個月一次、或約每年一次。基於抗體的藥物之調配係在所屬技術領域中的通常技術內。The amount administered will depend on variables such as the type and extent of the disease or indication to be treated, the overall health of the patient, the in vivo efficacy of the antibody, the pharmaceutical formulation, and the route of administration. The initial dose can be increased beyond the upper limit level to quickly reach the desired blood level or tissue level. Alternatively, the initial dose can be made less than the optimal value, and the dose can be gradually increased during the course of the treatment. The human dose can be optimized, for example, in a conventional phase I dose escalation study that is designed to, for example, be carried out at 0.5 mg/kg to 20 mg/kg. The frequency of administration may vary based on factors such as the route of administration, dosage, and the disease being treated. Exemplary dosing frequency is more than once a day, about once a day, about twice a day, about three times a day, about four times a day, about five times a day, about every other day, about every second day , About once a week, about once every two weeks, about once a month, about once every two months, about once every three months, about once every six months, or about once a year. The formulation of antibody-based drugs is within the usual techniques in the technical field.

於各種實施方式中，可長期投予本發明之抗體。例如，可投予該等抗體至少約1週、至少約4週、約8週、或至少約12週。於一些實施方式中，攝生法係達至少約1個月、至少約6個月、至少約12個月、至少約1年、至少約2年、至少約3年、至少約4年、至少約5年、至少約6年、至少約7年、至少約8年、至少約9年、至少約10年、至少約15年、至少約20年、至少約30年、至少約40年、或至少約50年。In various embodiments, the antibody of the present invention can be administered for a long period of time. For example, the antibodies can be administered for at least about 1 week, at least about 4 weeks, about 8 weeks, or at least about 12 weeks. In some embodiments, the regimen of hygiene is at least about 1 month, at least about 6 months, at least about 12 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 30 years, at least about 40 years, or at least About 50 years.

對於治療使用，抗體可與醫藥上可接受的載體組合。用於本文中，「醫藥上可接受的載體」意味適用於與人類及動物之組織接觸而無過度的毒性、刺激、過敏反應、或其他問題或併發症且與合理的效益/風險比率相稱的緩衝劑、載體、及賦形劑。該（等）載體應在與調配物之其他成分相容且對接受者而言非為有害的意義上為「可接受的」。醫藥上可接受的載體包括與醫藥投予相容的緩衝劑、溶劑、分散介質、塗層、等張及吸收延遲劑、及類似者。此等介質及劑對於醫藥活性物質的使用於所屬技術領域中係已知的。For therapeutic use, the antibody can be combined with a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" means suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and commensurate with a reasonable benefit/risk ratio Buffers, carriers, and excipients. The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient. Pharmaceutically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like compatible with pharmaceutical administration. The use of these media and agents for pharmaceutically active substances is known in the art.

含有抗體（諸如該等於本文中揭示者）的醫藥組成物可呈劑量單位形式及可以任何合適的方法製備。應將醫藥組成物調配成與其意欲的投予途徑相容。投予之途徑之實例為靜脈內（IV）、皮內、吸入、透皮、局部、透黏膜、及直腸投予。於一個實施方式中，用於本發明之抗體的投予之途徑係IV輸注。有用的調配物可藉由醫藥技術領域中廣為人知的方法製備。例如，參見Remington's Pharmaceutical Sciences , 18th ed.（Mack Publishing Company, 1990）。Pharmaceutical compositions containing antibodies (such as those disclosed herein) can be in dosage unit form and can be prepared by any suitable method. The pharmaceutical composition should be formulated to be compatible with its intended route of administration. Examples of routes of administration are intravenous (IV), intradermal, inhalation, transdermal, topical, transmucosal, and rectal administration. In one embodiment, the route for administration of the antibody of the present invention is IV infusion. Useful formulations can be prepared by methods well known in the medical technology field. For example, see Remington's Pharmaceutical Sciences , 18th ed. (Mack Publishing Company, 1990).

於一些實施方式中，將該等醫藥組成物調配成適用於口服投予的組成物。用於口服遞送的組成物可例如呈錠劑、菱形錠、水性或油性懸液劑、顆粒、散劑、分散型給藥小粒（sprinkle）、乳劑、膠囊、糖漿、或酏劑的形式。口服投予的組成物可包含一或多種例如甜味劑，諸如果糖、阿斯巴甜或糖精；矯味劑，諸如薄荷、冬綠油、或櫻桃；呈色劑；及保藏劑的劑以提供醫藥上可口的製劑。In some embodiments, these pharmaceutical compositions are formulated into compositions suitable for oral administration. The composition for oral delivery may, for example, be in the form of lozenges, lozenges, aqueous or oily suspensions, granules, powders, sprinkles, emulsions, capsules, syrups, or elixirs. The composition for oral administration may contain one or more agents such as sweeteners, such as fructose, aspartame, or saccharin; flavoring agents, such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives to provide Pharmaceutically delicious preparation.

於一些實施方式中，將該等醫藥組成物調配成適用於非經腸投予的組成物。適用於非經腸投予（例如靜脈內、皮下、肌內、或腹膜內注射及輸注）的劑型包括（例如）溶液、懸液劑、分散劑、乳劑、及類似者。其等亦可以可於緊鄰使用前溶解或懸浮在無菌可注射介質中的無菌固體組成物（例如凍乾組成物）的形式製造。其等可含有（例如）懸浮劑或分散劑。In some embodiments, these pharmaceutical compositions are formulated into compositions suitable for parenteral administration. Dosage forms suitable for parenteral administration (such as intravenous, subcutaneous, intramuscular, or intraperitoneal injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They can also be manufactured in the form of a sterile solid composition (such as a lyophilized composition) that can be dissolved or suspended in a sterile injectable medium immediately before use. They may contain, for example, a suspending agent or a dispersing agent.

於一些實施方式中，該等組成物可另外包括醫藥上可接受的賦形劑或載體。例示性賦形劑包括檸檬酸鈉、磷酸二鈣、等等、及／或a）填料或增容劑，諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇、矽酸、微晶纖維素、及烘焙專用糖（Bakers Special Sugar）、等等、b）黏合劑，諸如（例如）羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖、阿拉伯膠、聚乙烯醇、聚乙烯聚吡咯啶酮、甲基纖維素、羥丙基纖維素（HPC）、及羥甲基纖維素等等、c）保濕劑，諸如甘油、等等、d）崩散劑，諸如瓊脂、碳酸鈣、馬鈴薯或樹薯澱粉、海藻酸、某些矽酸鹽、碳酸鈉、交聯聚合物，諸如交聯普維酮（crospovidone）（交聯聚乙烯吡咯啶酮）、croscarmellose鈉（交聯羧甲基纖維素鈉）、乙醇酸鈉澱粉、等等、e）溶液阻滯劑，諸如石蠟、等等、f）吸收加速劑，諸如四級銨化合物、等等、g）潤濕劑，諸如（例如）鯨蠟醇及甘油單硬脂酸酯、等等、h）吸收劑，諸如高嶺土及膨潤土、等等、及i）潤滑劑，諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉、甘油二十二酸酯、等等、及此等賦形劑之混合物。所屬技術領域中具有通常知識者會認知到特定的賦形劑可具有二或多種功能。In some embodiments, the compositions may additionally include pharmaceutically acceptable excipients or carriers. Exemplary excipients include sodium citrate, dicalcium phosphate, etc., and/or a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose, and baking Bakers Special Sugar, etc., b) Binders such as (for example) carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, polyvinyl alcohol, polyvinyl poly Pyrolidone, methyl cellulose, hydroxypropyl cellulose (HPC), and hydroxymethyl cellulose, etc., c) humectant, such as glycerin, etc., d) disintegrating agent, such as agar, calcium carbonate, potato Or tapioca starch, alginic acid, certain silicates, sodium carbonate, cross-linked polymers, such as crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked carboxymethyl fiber Sodium), sodium glycolate starch, etc., e) solution blockers, such as paraffin, etc., f) absorption accelerators, such as quaternary ammonium compounds, etc., g) wetting agents, such as (for example) Cetyl alcohol and glycerol monostearate, etc., h) absorbents, such as kaolin and bentonite, etc., and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene Alcohol, sodium lauryl sulfate, glyceryl behenate, etc., and mixtures of these excipients. Those skilled in the art will recognize that specific excipients can have two or more functions.

醫藥調配物較佳係無菌的。滅菌可（例如）藉由過濾通過無菌過濾膜來完成。在組成物被凍乾的情況下，過濾器滅菌可在凍乾及復水之前或之後實施。實施例 實施例1. HIV CrossMab抗體之構築及特徵界定The pharmaceutical formulation is preferably sterile. Sterilization can be accomplished, for example, by filtering through a sterile filter membrane. In the case where the composition is lyophilized, filter sterilization can be performed before or after lyophilization and rehydration. Examples Example 1. Construction and characterization of HIV CrossMab antibody

圖[[13]] 13A-E及圖14A-E [[14]]展示一些基於iMab的CrossMab相較於親本Ab具有較大的效力及廣度。除非另外指出，所有基於iMab的雙專一性抗體皆使用MV1變體構築。IC80（賦予80%的病毒感染性之中和的抗體濃度）係一種評估抗體對抗HIV的效力的方法。IC80數字越低（在圖之y軸以抗體濃度（μg/ml）的形式顯示），抗體中和特定HIV病毒株或分離株的效力越強。IC50（賦予50%的病毒感染性之中和的抗體濃度）係另一種評估抗體對抗HIV的效力的方法。IC50數字越低（在圖之y軸以抗體濃度（μg/ml）的形式顯示），抗體中和特定HIV病毒株或分離株的效力越強。Figures [[13]] 13A-E and Figure 14A-E [[14]] show that some iMab-based CrossMabs have greater potency and breadth than parent Abs. Unless otherwise noted, all iMab-based bispecific antibodies are constructed using MV1 variants. IC80 (antibody concentration that confers 80% neutralization of viral infectivity) is a method for evaluating the effectiveness of antibodies against HIV. The lower the IC80 number (shown in the form of antibody concentration (μg/ml) on the y-axis of the graph), the stronger the antibody's ability to neutralize a specific HIV strain or isolate. IC50 (the concentration of antibody that confers 50% neutralization of viral infectivity) is another method for evaluating the effectiveness of antibodies against HIV. The lower the IC50 number (shown in the form of antibody concentration (μg/ml) on the y-axis of the graph), the stronger the antibody's ability to neutralize a specific HIV strain or isolate.

針對一大組HIV-1假病毒（118種不同的HIV病毒分離株）（其等對於HIV套膜在地理、演化支、向性、及感染期的多樣性有代表性）測試各種對的抗體。使用IC80及IC50以評估抗病毒效力及廣度之強度。圖13E及14E清楚展示相較於親本抗體iMab及10E8，兩者一起的雙專一性CrossMab（10E8/iMab）更有效地中和幾乎所有HIV病毒（各病毒係以點的形式顯示）。其他抗體對（用以製作145/iMab、117/iMab、128/iMab及151/iMab）相較於其等之親本組份有時增強HIV效力而有時則否。Test various pairs of antibodies against a large group of HIV-1 pseudoviruses (118 different HIV virus isolates) (which are representative for the diversity of HIV mantle in geography, evolution, tropism, and infection period) . Use IC80 and IC50 to evaluate the strength of antiviral efficacy and breadth. Figures 13E and 14E clearly show that compared to the parental antibodies iMab and 10E8, the dual specific CrossMab (10E8/iMab) neutralizes almost all HIV viruses more effectively (each virus line is shown in the form of dots). Other antibody pairs (used to make 145/iMab, 117/iMab, 128/iMab, and 151/iMab) sometimes enhance HIV efficacy compared to their parental components and sometimes not.

如於圖15A-E中顯示的，抗體iMab於細胞-細胞中和檢定中亦係相對有效的。PGT145、3BNC117、10E8、PGT128及PGT151在中和無細胞病毒感染方面係相對有效的，但於細胞-細胞傳播檢定中在中和病毒方面係差的。創造包括PGT145、3BNC117、10E8、PGT128及PGT151結合iMab的雙專一性抗體使此等嵌合抗體於細胞-細胞傳播檢定中在中和病毒方面有活性。可見到10E8/iMab於此等比較性研究中係最有效力的抗體。亦發現到10E8/iMab於試管內預防細胞-細胞傳播方面最有活性。As shown in Figures 15A-E, the antibody iMab is also relatively effective in cell-cell neutralization assays. PGT145, 3BNC117, 10E8, PGT128, and PGT151 are relatively effective in neutralizing cell-free virus infection, but are poor in neutralizing virus in the cell-cell transmission test. The creation of bispecific antibodies including PGT145, 3BNC117, 10E8, PGT128 and PGT151 combined with iMab makes these chimeric antibodies active in neutralizing viruses in cell-cell transmission assays. It can be seen that 10E8/iMab is the most effective antibody in these comparative studies. It was also found that 10E8/iMab is the most active in preventing cell-cell spread in the test tube.

如於圖16中闡明的，10E8/iMab之改善的效力係統計上顯著的。圖3顯示改善的效力需要抗體之共價連結，即CrossMab形式（因為兩種親本抗體（iMab及10E8）之共投予相較於經融合且物理上連接的雙專一性10E8/iMab抗體提供較低的MPI）。圖10、11A-E、12A-E、13A-E、及14A-E提供源自iMab的CrossMab抗體相較於其親本抗體的改善的效力之進一步證據。As illustrated in Figure 16, the improved effectiveness of 10E8/iMab is systematically significant. Figure 3 shows that improved efficacy requires the covalent linkage of the antibody, the CrossMab format (because the co-administration of the two parent antibodies (iMab and 10E8) provides compared to the fused and physically linked bispecific 10E8/iMab antibody Lower MPI). Figures 10, 11A-E, 12A-E, 13A-E, and 14A-E provide further evidence of the improved efficacy of the iMab-derived CrossMab antibody compared to its parent antibody.

總而言之，發現到對於基於iMab的CrossMab（與PGT145、3BNC117、PGT151、PGT128及10E8融合）而言，117/iMab改善廣度但非效力；145/iMab、151/iMab及128/iMab改善廣度及效力；且10E8/iMab顯著地改善廣度及效力。關於表位定位/可及性及中和之效力模型，10E8/iMab似乎展現附著前及附著後中和；145/iMab、151/iMab及117/iMab似乎展現附著前中和；且117/iMab對於一些病毒可能顯示立體限制之跡象及可能減低的效力。10E8/iMab亦展現對抗HIV細胞至細胞傳播的有效活性。In summary, it was found that for iMab-based CrossMab (integrated with PGT145, 3BNC117, PGT151, PGT128 and 10E8), 117/iMab improved breadth but not effectiveness; 145/iMab, 151/iMab and 128/iMab improved breadth and effectiveness; And 10E8/iMab significantly improves the breadth and effectiveness. Regarding the efficacy model of epitope localization/accessibility and neutralization, 10E8/iMab seems to exhibit pre-attachment and post-attachment neutralization; 145/iMab, 151/iMab and 117/iMab seem to exhibit pre-attachment neutralization; and 117/iMab For some viruses, it may show signs of three-dimensional restriction and possibly reduced effectiveness. 10E8/iMab also exhibits effective activity against HIV cell-to-cell transmission.

如亦於圖13A-D及14A-D中顯示的，基於Pro 140的CrossMab之活性有時比其等之親本抗體及相對應的基於iMab的CrossMab弱，如達到IC80及IC50所需的高濃度所顯示的。透過稱為Pro 140的另一種宿主細胞受體結合性抗體將此四種mAb錨定至宿主細胞受體CCR5相較於其等各別的親本抗體並未改善抗病毒效力或廣度（如由對抗一大組HIV分離株的IC80測量的）。此等組顯示對於此四種抗體的基於Pro140的CrossMab相較於其等之相對應的基於iMab的CrossMab係較弱的（基於Pro140者vs基於iMab的CrossMab之IC50及IC80比較）。As also shown in Figures 13A-D and 14A-D, the activity of Pro 140-based CrossMab is sometimes weaker than its parental antibody and the corresponding iMab-based CrossMab, such as the high required to achieve IC80 and IC50. The concentration is displayed. The anchoring of these four mAbs to the host cell receptor CCR5 through another host cell receptor binding antibody called Pro 140 did not improve the antiviral efficacy or breadth compared to their respective parent antibodies (such as IC80 against a large group of HIV isolates). These groups show that the Pro140-based CrossMab for these four antibodies is weaker than the corresponding iMab-based CrossMab (comparison of IC50 and IC80 for Pro140-based vs. iMab-based CrossMab).

如於圖13E及14E中顯示的，10E8/P140（第五種基於Pro 140的CrossMab）相較於其親本抗體及10E8/iMab CrossMab更有效。此等組闡明親本mAb Pro140（圖13E及14E中的數據點之最右欄）、雙專一性CrossMab 10E8/P140（圖13E及14E中的數據點之右起第二欄）、及親本mAb 10E8（圖13E及14E中的數據點之中央欄）對抗一大組HIV分離株的效力（IC80或IC50）之比較。此等組亦闡明親本mAb iMab（圖13E及14E中的數據點之最左欄）、雙專一性CrossMab 10E8/iMab（圖13E及14E中的數據點之左起第二欄）、及親本mAb 10E8（圖13E及14E中的數據點之中央欄）對抗一大組HIV分離株的效力（IC80或IC50）之比較。圖13E及14E中的數據點之左起第二及右起第二欄闡明雙專一性CrossMab 10E8/iMab及10E8/P140對抗一大組HIV分離株的效力（IC80或IC50）之比較。As shown in Figures 13E and 14E, 10E8/P140 (the fifth Pro 140-based CrossMab) is more effective than its parent antibody and 10E8/iMab CrossMab. These groups illustrate the parent mAb Pro140 (the rightmost column of the data points in Figures 13E and 14E), the dual specificity CrossMab 10E8/P140 (the second column from the right of the data points in Figures 13E and 14E), and the parent Comparison of the efficacy (IC80 or IC50) of mAb 10E8 (the center column of the data points in Figures 13E and 14E) against a large group of HIV isolates. These groups also illustrate the parental mAb iMab (the leftmost column of the data points in Figures 13E and 14E), the dual specificity CrossMab 10E8/iMab (the second column from the left of the data points in Figures 13E and 14E), and the parent Comparison of the efficacy (IC80 or IC50) of this mAb 10E8 (the center column of the data points in Figures 13E and 14E) against a large group of HIV isolates. The second column from the left and the second column from the right of the data points in Figures 13E and 14E illustrate the comparison of the efficacy (IC80 or IC50) of the dual specific CrossMab 10E8/iMab and 10E8/P140 against a large group of HIV isolates.

已知Pro 140不具有對抗X4 HIV病毒的活性，因為X4病毒使用CXCR4作為用於HIV-1進入的輔受體，而Pro 140與CCR5結合。單獨10E8具有非常弱的對抗X4病毒的活性。然而，雙專一性CrossMab 10E8/Pro 140相較於任一其親本抗體可更好地中和迄今測試的所有X4病毒。圖4A-J闡明10E8、Pro 140、及10E8/P140雙專一性CrossMab抗體於HIV之各種病毒株之抑制的有效性。It is known that Pro 140 does not have activity against X4 HIV virus because X4 virus uses CXCR4 as a co-receptor for HIV-1 entry, and Pro 140 binds to CCR5. 10E8 alone has very weak activity against the X4 virus. However, the dual specificity CrossMab 10E8/Pro 140 can better neutralize all X4 viruses tested so far than any of its parent antibodies. Figures 4A-J illustrate the effectiveness of 10E8, Pro 140, and 10E8/P140 bispecific CrossMab antibodies in inhibiting various strains of HIV.

如於圖5A-G中顯示的，10E8/Pro140 CrossMab相較於其兩種親本抗體之共投予係HIV之各種病毒株之更有效抑制劑，展示此特定雙專一性抗體之效力之增效性（而不只是累加性）增強。As shown in Figures 5A-G, 10E8/Pro140 CrossMab is a more effective inhibitor than the co-administration of its two parental antibodies to various strains of HIV, demonstrating the increased potency of this specific bispecific antibody. Effectiveness (not just additive) is enhanced.

如於圖6A-D中顯示的，融合至非膜結合性抗體（X19）的10E8的CrossMab並未提供增強的效力，如當與膜結合性10E8/P140作比較時可見的。因此，10E8/P140 CrossMab之效力似乎需要10E8至細胞膜之錨定。然而，單獨膜結合並未提供此等CrossMab之增強的效力。圖7A-H顯示將10E8錨定在HER2上相較於將10E8錨定在CCR5上並未提供實質上的效力增強。10E8至病毒受體的專一性錨定（於此例子中為CCR5（透過Pro 140）或CD4（透過iMab））提供增強的抗病毒活性。As shown in Figures 6A-D, the CrossMab of 10E8 fused to the non-membrane-bound antibody (X19) did not provide enhanced efficacy, as can be seen when compared to membrane-bound 10E8/P140. Therefore, the effectiveness of 10E8/P140 CrossMab seems to require anchoring of 10E8 to the cell membrane. However, membrane binding alone does not provide the enhanced efficacy of these CrossMabs. Figures 7A-H show that anchoring 10E8 to HER2 does not provide a substantial potency enhancement compared to anchoring 10E8 to CCR5. The specific anchoring of 10E8 to the viral receptor (in this example, CCR5 (via Pro 140) or CD4 (via iMab)) provides enhanced antiviral activity.

D10E8係10E8 mAb之突變體版本，其於輕鏈FR3具有一個胺基酸缺失。相較於10E8，D10E8具有遠較弱的表位結合活性，如於圖8A-C中闡明的。然而，一旦D10E8被錨定在細胞受體上（藉由於CrossMab抗體中組合D10E8及iMab- iMab專一性地結合細胞受體CD4），圖8D-E顯示其抑制活性被改善。此等數據暗示專一性細胞受體錨定（即錨定在病毒受體或病毒輔受體上）於增強此HIV抗體之活性的貢獻。又，雖然D10E8/P140 CrossMab相較於D10E8具有改善的抗病毒活性，其相較於10E8/P140 CrossMab效力仍較差。D10E8/P140 CrossMab在中和R5病毒方面相較於中和X4病毒係相對更有效的。D10E8 is a mutant version of 10E8 mAb, which has an amino acid deletion in the light chain FR3. Compared to 10E8, D10E8 has far weaker epitope binding activity, as illustrated in Figures 8A-C. However, once D10E8 is anchored to the cell receptor (due to the combination of D10E8 and iMab-iMab in the CrossMab antibody specifically binds to the cell receptor CD4), Figure 8D-E shows that its inhibitory activity is improved. These data suggest the contribution of specific cell receptor anchoring (ie anchoring to viral receptors or viral co-receptors) in enhancing the activity of this HIV antibody. Also, although D10E8/P140 CrossMab has improved antiviral activity compared to D10E8, its efficacy is still poorer than that of 10E8/P140 CrossMab. D10E8/P140 CrossMab is relatively more effective in neutralizing R5 virus than X4 virus.

4E10係抗gp41 MPER mAb，其已知相較於抗gp41 MPER mAb 10E8效力較差。類似於針對D10E8所得的結果，圖20及21A-G顯示錨定4E10在輔受體CCR5上（透過CrossMab抗體中的Pro 140）顯著地增強4E10之抗病毒活性。一起，此暗示一些抗gp41 MPER Ab至CCR5或CD4的錨定（透過在CrossMab抗體雙專一性中組合MPER Ab與P140或iMab）可大大地改善各別抗gp41 MPER Ab之效力及廣度。4E10 is an anti-gp41 MPER mAb, which is known to be less effective than anti-gp41 MPER mAb 10E8. Similar to the results obtained for D10E8, Figures 20 and 21A-G show that anchoring 4E10 on the co-receptor CCR5 (through Pro 140 in the CrossMab antibody) significantly enhances the antiviral activity of 4E10. Together, this implies that the anchoring of some anti-gp41 MPER Ab to CCR5 or CD4 (by combining MPER Ab with P140 or iMab in the CrossMab antibody bispecificity) can greatly improve the potency and breadth of the respective anti-gp41 MPER Ab.

多個參數導致某些雙專一性CrossMab對抗HIV的增強的活性，包括親本Ab效力、親和力、及附著前及附著後中和能力。特別地，10E8/Pro140 CrossMab在以下方面代表了有效的組合：克服能量性、空間性及時間性限制、進入程序中的靶向性依序性／相互依存性步驟、表位定位／可及性、結合親和力、附著前及附著後中和、及結合幾何。如於圖20中顯示的，4E10/Pro140相較於D10E8/Pro140及10E8/Pro140具有較大的對於MPER的結合親和力。圖9A-G顯示10E8/Pro140、D10E8/Pro140及4E10/Pro140、及其等之親本抗體10E8、D10E8及4E10對抗HIV之各種病毒株的抑制效力。圖10、13A-E、14A-E、15A-E、16、及17A-B提供CrossMab抗體相較於其等之個別的親本抗體及親本抗體之組合的較大的效力之另外的證據。Multiple parameters lead to the enhanced activity of certain bispecific CrossMabs against HIV, including parental Ab potency, affinity, and pre-attachment and post-attachment neutralization capabilities. In particular, 10E8/Pro140 CrossMab represents an effective combination in the following aspects: overcoming energy, spatial and temporal constraints, targeted sequence/interdependence steps in the entry procedure, epitope location/accessibility , Binding affinity, neutralization before and after attachment, and binding geometry. As shown in Figure 20, 4E10/Pro140 has a greater binding affinity for MPER than D10E8/Pro140 and 10E8/Pro140. Figures 9A-G show the inhibitory efficacy of 10E8/Pro140, D10E8/Pro140 and 4E10/Pro140, and their parent antibodies 10E8, D10E8 and 4E10 against various strains of HIV. Figures 10, 13A-E, 14A-E, 15A-E, 16, and 17A-B provide additional evidence of the greater efficacy of CrossMab antibodies compared to their individual parent antibodies and combinations of parent antibodies .

10E8/iMab及10E8/Pro140 CrossMab之增強的抗病毒涵蓋範圍係於圖10中闡明，而圖10描繪數種抗體對抗HIV的效力及廣度。圖中的x軸指出特定抗體之濃度，y軸指出被特定濃度的特定抗體中和的一大組HIV病毒分離株之百分比，且各線指出所評估的不同抗體。沿著x軸的最左邊的線及在y軸上可接近達到100%或達到100%者指出對抗HIV有高度效力及廣度的抗體。10E8/P140 CrossMab及10E8/iMab CrossMab在病毒涵蓋範圍及效力兩方面皆屬於最有效的抗體，且相較於其等之親本抗體明顯更有效。The enhanced antiviral coverage of 10E8/iMab and 10E8/Pro140 CrossMab is illustrated in Figure 10, and Figure 10 depicts the effectiveness and breadth of several antibodies against HIV. The x-axis in the figure indicates the concentration of a specific antibody, the y-axis indicates the percentage of a large group of HIV virus isolates neutralized by a specific antibody at a specific concentration, and each line indicates the different antibodies evaluated. The leftmost line along the x-axis and those close to 100% or 100% on the y-axis indicate antibodies with high efficacy and breadth against HIV. 10E8/P140 CrossMab and 10E8/iMab CrossMab are the most effective antibodies in terms of virus coverage and efficacy, and are significantly more effective than their parental antibodies.

圖18A-H及19A-C顯示CrossMab 10E8/515H7抗體相較於其親本抗體及先前討論的抗體的效力。CrossMab抗體之效力似乎不與細胞膜蛋白質目標之密度直接相關，因為CCR5（Pro140之目標）之密度低於CD4（ibalizumab之目標）之密度，但源自10E8/Pro140的CrossMab抗體之效力大於源自10E8/ iMab的CrossMab抗體之效力。Figures 18A-H and 19A-C show the efficacy of the CrossMab 10E8/515H7 antibody compared to its parent antibody and the previously discussed antibodies. The efficacy of CrossMab antibody does not seem to be directly related to the density of cell membrane protein targets, because the density of CCR5 (target of Pro140) is lower than that of CD4 (target of ibalizumab), but the efficacy of CrossMab antibody derived from 10E8/Pro140 is greater than that of 10E8 / The effectiveness of iMab's CrossMab antibody.

如於圖22A-B中顯示的，於粒徑篩析層析法中的單一尖銳峰之缺乏對於源自10E8及10E8的CrossMab抗體顯示一種表明多種分子物種的不穩定性。表1敘述用以解決10E8不穩定性的各種程序及調配修改。然而，如於SEC或粒徑篩析層析法欄中的「X」顯示的，該等修改於提供單一尖銳峰方面不成功。 表1：欲解決10E8不穩定性的程序及調配篩選

Figure 107146176-A0304-0001
As shown in Figure 22A-B, the lack of a single sharp peak in particle size sieve analysis chromatography shows an instability that indicates multiple molecular species for CrossMab antibodies derived from 10E8 and 10E8. Table 1 describes various procedures and deployment modifications to solve the instability of 10E8. However, as indicated by the "X" in the SEC or particle size sieving chromatography column, these modifications were unsuccessful in providing a single sharp peak. Table 1: To solve the 10E8 instability procedures and deployment screening
Figure 107146176-A0304-0001

如於圖23中顯示的，配對10E8重鏈與4E10之輕鏈解決此不穩定性問題，產生功能性（雖然效力較差）的抗體。此結果顯示10E8之不穩定性係導因於其輕鏈。10E8輕鏈之各種修改（於圖24B-C中顯示，諸如C端絲胺酸之移除、工程設計λ-可變區及κ-恆定區嵌合體、工程設計在10E8重鏈及輕鏈間的額外雙硫鍵、或將非10E8抗體之κ輕鏈區域基因嫁接至10E8輕鏈上）並未完全解決10E8不穩定性。如於圖25及26A-B中顯示的，該不穩定性可能係導因於10E8之互補性決定區（「CDR」）及骨架區（「FW」）之組合。使用10E8-HC/4E10-LC，各個10E8輕鏈CDR被個別或一起嫁接至4E10LC上，如於圖25中顯示的。10E8 LC CDR2及CDR3之添加被良好地容忍，但10E8 LC CDR1之添加瓦解單一峰。當所有的10E8 CDR皆被嫁接至4E10時，其峰係寬的。將10E8 CDR或骨架嫁接至其生殖細胞系輕鏈l上導致單一峰，如於圖26A中顯示的，但於MPER結合及HIV中和方面的有效性減低。表2概述所測試的10E8輕鏈變體及其等之效力。 表2：所產生的10E8 LC變體

Figure 107146176-A0304-0002
As shown in Figure 23, pairing the 10E8 heavy chain with the 4E10 light chain solves this instability problem and produces a functional (albeit less potent) antibody. This result shows that the instability of 10E8 is due to its light chain. Various modifications of 10E8 light chain (shown in Figure 24B-C, such as the removal of C-terminal serine, engineering design of λ-variable region and κ-constant region chimera, engineering design between 10E8 heavy chain and light chain The additional disulfide bonds, or the grafting of the κ light chain region gene of the non-10E8 antibody to the 10E8 light chain) did not completely solve the 10E8 instability. As shown in Figures 25 and 26A-B, this instability may be due to the combination of the complementarity determining region ("CDR") and framework region ("FW") of 10E8. Using 10E8-HC/4E10-LC, each 10E8 light chain CDR was grafted onto 4E10LC individually or together, as shown in FIG. 25. The addition of 10E8 LC CDR2 and CDR3 was well tolerated, but the addition of 10E8 LC CDR1 broke the single peak. When all 10E8 CDRs are grafted to 4E10, the peaks are broad. Grafting the 10E8 CDR or backbone to its germ cell line light chain 1 resulted in a single peak, as shown in Figure 26A, but was less effective in MPER binding and HIV neutralization. Table 2 summarizes the 10E8 light chain variants tested and their efficacy. Table 2: 10E8 LC variants produced
Figure 107146176-A0304-0002

發現10E8抗體之變體H6L10為活性且非自體反應性的，且按粒徑篩析層析法係穩定的，如於圖27中顯示的。發現H6L10/Pro 140及其親本抗體於小鼠中具有可相較的藥動學輪廓，如於圖28中顯示的。然而，如於圖29中顯示的，當針對一大組HIV病毒株作測試時，在雙專一性抗體中與P140的組合的10E8之H6L10變體（亦稱為10E8v 1.0 ）相較於10E8/P140效力實質上較差。當針對抗一大組HIV病毒株作測試時，在雙專一性抗體中與iMab組合的10E8之H6L10變體（稱為10E8v 1.0 ）相較於10E8/iMab維持相同的效力之相對量，但10E8v 1.0/iMab具有與10E8/iMab相同的不穩定性，如由粒徑篩析層析法測定及由表3中的X指出的。於一個實施方式中，該H6L10變體可進一步包括S74W突變。The variant H6L10 of the 10E8 antibody was found to be active and non-autoreactive, and stable by particle size sieving chromatography, as shown in Figure 27. It was found that H6L10/Pro 140 and its parent antibody have comparable pharmacokinetic profiles in mice, as shown in Figure 28. However, as shown in Figure 29, when tested against a large group of HIV strains, the H6L10 variant of 10E8 in combination with P140 in the bispecific antibody (also known as 10E8 v1.0 ) compared to 10E8 /P140 is substantially less effective. When tested against a large group of HIV strains, the H6L10 variant of 10E8 combined with iMab in the bispecific antibody (referred to as 10E8 v 1.0 ) maintained the same relative amount of potency compared to 10E8/iMab, but 10E8v 1.0/iMab has the same instability as 10E8/iMab, as determined by particle size sieve chromatography and indicated by X in Table 3. In one embodiment, the H6L10 variant may further include a S74W mutation.

以下表3列舉例示性變體、其等之活性、粒徑篩析層析法結果、及藥動學（「PK」）結果（亦參見圖46）。 表3：為穩定且同時維持抗HIV活性的例示性變體

Figure 107146176-A0304-0003
The following Table 3 lists exemplary variants, their activities, particle size screening chromatography results, and pharmacokinetics ("PK") results (see also Figure 46). Table 3: Exemplary variants that are stable while maintaining anti-HIV activity
Figure 107146176-A0304-0003

如以上指出的，10E8V1.0 係稱為H6L10的10E8之體細胞變體。身為mAb，H6L10按SEC具有單一峰但相較於10E8活性減低。H6L10/Pro140 CrossMab具有單一SEC峰及良好的小鼠PK，但抗HIV活性減低。H6L10/iMab CrossMab具有二重SEC峰及差的小鼠PK，但其對抗HIV的活性與10E8/iMab大致相同。10E8V1.1 於H6L10包括單一點突變。當在CrossMab雙專一性中與Pro140配對時，此構築體具有單一SEC峰及良好的小鼠PK。其對抗HIV的活性相較於10E8V1.0/Pro140被改善，但仍然稍低於10E8/Pro140之活性。當在CrossMab雙專一性中與iMab配對時，此構築體具有二重SEC峰及差的小鼠PK，且其對抗HIV的活性仍然與10E8/iMab及10E8V1.0/iMab大致相同。10E8V2.0 係10E8之嵌合抗體變體，其中FW1、CDR1及FW2之部分係來自10E8V1.0 且其中FW2之剩下的部分、CDR2、FW3、CDR3及FW4係來自10E8。當在CrossMab雙專一性中與Pro140配對時，此構築體具有二重SEC峰且相較於10E8/Pro140對抗HIV的活性減低。當在CrossMab雙專一性中與iMab配對時，此構築體具有單一SEC峰及良好的PK，且相較於10E8/iMab對抗HIV的活性改善。10E8V3.0 係稱為H11L1的10E8之體細胞變體。H11L1/Pro140 CrossMab具有單一SEC峰且相較於任何其他10E8/Pro140構築體（包括原始鑑認者）抗HIV活性較好，但由於自體反應性而具有差的小鼠PK。H11L1/iMab CrossMab具有單一SEC峰且相較於原始鑑認的10E8/iMab抗HIV活性較好且活性與在10E8V2.0 /iMab觀察到者大致相等，但由於自體反應性而具有差的小鼠PK。As noted above, 10E8 V1.0 is a somatic variant of 10E8 called H6L10. As a mAb, H6L10 has a single peak by SEC but has reduced activity compared to 10E8. H6L10/Pro140 CrossMab has a single SEC peak and good mouse PK, but its anti-HIV activity is reduced. H6L10/iMab CrossMab has a double SEC peak and poor mouse PK, but its anti-HIV activity is about the same as 10E8/iMab. 10E8 V1.1 includes a single point mutation in H6L10. When paired with Pro140 in CrossMab dual specificity, this construct has a single SEC peak and good mouse PK. Its anti-HIV activity is improved compared to 10E8V1.0/Pro140, but it is still slightly lower than that of 10E8/Pro140. When paired with iMab in the dual specificity of CrossMab, this construct has a double SEC peak and poor mouse PK, and its anti-HIV activity is still roughly the same as 10E8/iMab and 10E8V1.0/iMab. 10E8 V2.0 is a chimeric antibody variant of 10E8, in which the parts of FW1, CDR1 and FW2 are derived from 10E8 V1.0 and the remaining parts of FW2, CDR2, FW3, CDR3 and FW4 are derived from 10E8. When paired with Pro140 in the CrossMab dual specificity, this construct has a double SEC peak and is less active than 10E8/Pro140 against HIV. When paired with iMab in CrossMab dual specificity, this construct has a single SEC peak and a good PK, and its anti-HIV activity is improved compared to 10E8/iMab. 10E8 V3.0 is a somatic cell variant of 10E8 called H11L1. H11L1/Pro140 CrossMab has a single SEC peak and has better anti-HIV activity than any other 10E8/Pro140 constructs (including the original authenticator), but has poor mouse PK due to autoreactivity. H11L1/iMab CrossMab has a single SEC peak and has better anti-HIV activity than the originally identified 10E8/iMab, and the activity is roughly equal to that observed in 10E8 V2.0 /iMab, but it has poor autoreactivity. Mouse PK.

於特定CrossMab雙專一性之環境下產生單一SEC峰的10E8之變體當與Pro140或iMab配對時係不同的。顯現出此等CrossMab雙專一性抗體之10E8組之穩定性取決於環境且會基於其與之配對的抗體為何而變化。因此，鑑認出一種變體（10E8V1.1 ），其按SEC為穩定的且具有良好的小鼠PK且當與Pro140配對時具有良好的抗HIV活性。亦鑑認出另一種變體（10E8V2.0 ），其按SEC為穩定的且具有良好的小鼠PK且相較於原始鑑認的10E8/iMab具有較好的抗HIV活性。The 10E8 variant that produces a single SEC peak in a specific CrossMab dual specific environment is different when paired with Pro140 or iMab. The stability of the 10E8 group that exhibits these CrossMab bispecific antibodies depends on the environment and changes based on the antibodies they are paired with. Therefore, a variant (10E8 V1.1 ) was identified, which is stable by SEC and has good mouse PK and has good anti-HIV activity when paired with Pro140. Another variant (10E8 V2.0 ) was also identified, which is stable by SEC and has a good mouse PK and has better anti-HIV activity than the originally identified 10E8/iMab.

以下表4描述所測試的變體之自體反應性，其中「ANA」係指抗核活性且「ACA」係指抗心脂活性。 表4：試管內自體反應性評估

Figure 107146176-A0304-0004
Table 4 below describes the autoreactivity of the tested variants, where "ANA" refers to antinuclear activity and "ACA" refers to anticardiolipid activity. Table 4: Evaluation of autoreactivity in test tube
Figure 107146176-A0304-0004

圖30描繪10E8及得自數種10E8變體及iMab或P140的CrossMab抗體於小鼠模型中的藥動學。如於圖[[31]] 31A-D及32A-B [[32]]中顯示的，10E8v1.1 /P140及10E8v2.0 /iMab改善抗HIV活性及穩定性，且當於4°C下儲存在PBS中時具有良好的穩定性。圖33描繪10E8v2.0 /iMab（N297A）之天然質量光譜學分析。圖34A-C比較10E8v1.1 /P140及10E8v2.0 /iMab之對HIV演化支C組的活性，及比較其等之IC50及IC80效力。圖35及36比較10E8v1.1 /P140、10E8v2.0 /iMab、及各種單株抗體對抗HIV的效力。 實施例2.具有改善的溶解度、穩定性、及／或效力的HIV CrossMab抗體之開發Figure 30 depicts the pharmacokinetics of 10E8 and CrossMab antibodies derived from several 10E8 variants and iMab or P140 in a mouse model. As shown in Figures [[31]] 31A-D and 32A-B [[32]], 10E8 v1.1 /P140 and 10E8 v2.0 /iMab improve anti-HIV activity and stability, and are equivalent to 4° It has good stability when stored in PBS at C. Figure 33 depicts the natural mass spectroscopy analysis of 10E8 v2.0 /iMab (N297A). Figure 34A-C compares the activity of 10E8 v1.1 /P140 and 10E8 v2.0 /iMab on the HIV C-group, and compares their IC50 and IC80 efficacies. Figures 35 and 36 compare the efficacy of 10E8 v1.1 /P140, 10E8 v2.0 /iMab, and various monoclonal antibodies against HIV. Example 2. Development of HIV CrossMab antibody with improved solubility, stability, and/or efficacy

進行實驗以開發具有改善的溶解度、穩定性、及活性的10E8/iMab CrossMab抗體。Experiments were performed to develop 10E8/iMab CrossMab antibodies with improved solubility, stability, and activity.

一開始，在10E8.2/iMab抗體（亦稱為10E8v2.0 /iMab抗體）之表面上鑑認出一些疏水性殘基，其等可能負面地影響該雙專一性抗體之溶解度及穩定性。該等疏水性殘基係於以下表5呈現（參照Kabat編號系統）： 表5.

Figure 107146176-A0304-0005
At the beginning, some hydrophobic residues were identified on the surface of 10E8.2/iMab antibody (also known as 10E8 v2.0 /iMab antibody), which may negatively affect the solubility and stability of the bispecific antibody . The hydrophobic residues are presented in Table 5 below (refer to the Kabat numbering system): Table 5.
Figure 107146176-A0304-0005

使該等疏水性殘基單獨突變或組合突變以產生10E8.2/iMab變體並針對其等對抗HIV的功能活性及活體內藥動學輪廓作評估（參見圖37A-B）。該等各種10E8.2/iMab變體之胺基酸序列係於本文中在其他地方提供。These hydrophobic residues were mutated individually or in combination to generate 10E8.2/iMab variants and evaluated for their functional activity against HIV and in vivo pharmacokinetic profile (see Figure 37A-B). The amino acid sequences of these various 10E8.2/iMab variants are provided elsewhere herein.

具體言之，進行試管內中和檢定以測試10E8.2/iMab變體對抗HIV的活性。假病毒係如先前於Sun等人2014. JAIDS. 66, 473–483中描述地製備。病毒中和係以單一輪檢定使用TZM-bl細胞及HIV-1假病毒如先前描述地（Seaman等人2010. J. Virol. 84, 1439-1452）評估。如於圖37A中顯示的， 10E8.2/iMab變體中的一些（例如10E8.2.1/iMab、10E8.2.2/iMab、及10E8.2.3/iMab抗體）相較於親本10E8.2/iMab抗體在試管內HIV-1中和檢定維持功能活性。Specifically, an in-tube neutralization assay was performed to test the activity of the 10E8.2/iMab variant against HIV. The pseudovirus was prepared as previously described in Sun et al. 2014. JAIDS. 66, 473-483. The virus neutralization line was evaluated in a single round of assay using TZM-bl cells and HIV-1 pseudovirus as previously described (Seaman et al. 2010. J. Virol. 84, 1439-1452). As shown in Figure 37A, some of the 10E8.2/iMab variants (such as 10E8.2.1/iMab, 10E8.2.2/iMab, and 10E8.2.3/iMab antibody) are compared to the parental 10E8.2/iMab The antibody neutralizes the HIV-1 test to maintain functional activity in the test tube.

對於活體內藥動學分析，將BALB/c小鼠分成每組三隻的數組，並對各組中的小鼠腹膜內投予100 µg的所指出的抗體。於抗體投予後第1、2、4、7及10日自每隻動物抽取血液，並分離血清以及針對個別小鼠中的抗體之水平分析之。將CoStar 96槽孔EIA/RIA盤子於4°C下以每槽孔100 ng的山羊抗人類IgG Fc-γ片段塗覆過夜。將盤子以PBS + Tween洗滌三次並於室溫下以含有5%牛乳及0.5% BSA的PBS封阻2小時。將來自經處理動物的小鼠血清（及用於標準曲線的在PBS中的經純化抗體）以在含有2%牛乳及0.2% BSA的PBS中的1:2系列稀釋加至該等槽孔並培養2小時。於洗滌後，於室溫下將連接過氧化酶的山羊抗人類IgG培養1小時。以TMB液體受質系統（Liquid Substrate System）偵測樣本並於450 nm進行分光光度讀取。如於圖37B中顯示的，10E8.2/iMab變體中的一些（例如10E8.2.1/iMab、10E8.2.2/iMab、及10E8.2.3/iMab抗體）展現與親本10E8.2/iMab抗體類似的藥動學輪廓。For in vivo pharmacokinetic analysis, BALB/c mice were divided into groups of three each, and 100 µg of the indicated antibody was intraperitoneally administered to the mice in each group. Blood was drawn from each animal on the 1, 2, 4, 7 and 10 days after antibody administration, and the serum was separated and analyzed for the level of antibodies in individual mice. CoStar 96-well EIA/RIA plates were coated with 100 ng goat anti-human IgG Fc-γ fragments per well at 4°C overnight. The plate was washed three times with PBS + Tween and blocked with PBS containing 5% milk and 0.5% BSA at room temperature for 2 hours. The mouse serum from the treated animals (and the purified antibody in PBS used for the standard curve) was added to the wells in a 1:2 serial dilution in PBS containing 2% milk and 0.2% BSA. Incubate for 2 hours. After washing, peroxidase-linked goat anti-human IgG was incubated for 1 hour at room temperature. The TMB liquid substrate system (Liquid Substrate System) is used to detect the sample and perform a spectrophotometric reading at 450 nm. As shown in Figure 37B, some of the 10E8.2/iMab variants (e.g., 10E8.2.1/iMab, 10E8.2.2/iMab, and 10E8.2.3/iMab antibody) exhibited similarities to the parental 10E8.2/iMab antibody Similar pharmacokinetic profile.

此外，於熱壓力誘發性條件下評估該等變體之沈澱輪廓。具體言之，將10E8.2/iMab變體在293細胞中表現，使用蛋白質A管柱純化，交換至PBS（pH 7.4）之溶液中，並使用50 kDa的標稱分子量限制的膜濃縮至＞30 mg/mL。接著將樣本於50°C下培養並於所指出的時間點目測評估沈澱。來自熱壓力分析的結果係於圖37C中顯示。此等結果顯示10E8.2.3/iMab變體在熱壓力誘發性條件下維持試管內中和的有利抗病毒活性之最佳組合、有利的活體內藥動學、及增加的溶解度（減少的沈澱）。In addition, the precipitation profile of these variants was evaluated under thermal stress-induced conditions. Specifically, the 10E8.2/iMab variant was expressed in 293 cells, purified using a protein A column, exchanged into a solution of PBS (pH 7.4), and concentrated to> 30 mg/mL. The samples were then incubated at 50°C and the precipitation was assessed visually at the indicated time points. The results from the thermal pressure analysis are shown in Figure 37C. These results show that the 10E8.2.3/iMab variant maintains the best combination of beneficial antiviral activity for in vitro neutralization under thermal pressure induced conditions, favorable in vivo pharmacokinetics, and increased solubility (reduced precipitation) .

基於10E8.2.3/iMab於沈澱檢定中的有利特性，自此雙專一性抗體骨架變體創造另外的親水性變體及組合。此等新變體之各者係在於熱壓力誘發性條件下培養後藉由粒徑篩析層析法（SEC）評估其等之聚集可能性（參見圖38A-B）。具體言之，使用SEC以評估該等雙專一性抗體變體之物理化學同質性及以區分單體及非單體物種。結果顯示變體10E8.4/iMab及10E8.2.10/iMab展現最少的聚集，如由圖38B中在7 mL及11 mL間的減小的峰大小顯示的。進一步對10E8.4/iMab變體作另外的溶解度及穩定性研究。此變體相較於親本10E8.2/iMab抗體包含6個疏水性至親水性殘基突變的組合。圖45A-B提供親本10E8.2/iMab抗體及10E8.4/iMab變體之序列排比。Based on the advantageous properties of 10E8.2.3/iMab in precipitation assays, the bispecific antibody backbone variants have since created additional hydrophilic variants and combinations. Each of these new variants was cultured under thermal pressure-induced conditions and evaluated their aggregation potential by particle size analysis chromatography (SEC) (see Figure 38A-B). Specifically, SEC was used to assess the physicochemical homogeneity of the bispecific antibody variants and to distinguish between monomeric and non-monomer species. The results showed that the variants 10E8.4/iMab and 10E8.2.10/iMab exhibited the least aggregation, as shown by the reduced peak size between 7 mL and 11 mL in Figure 38B. Further solubility and stability studies of the 10E8.4/iMab variant were carried out. This variant contains a combination of 6 hydrophobic to hydrophilic residue mutations compared to the parental 10E8.2/iMab antibody. Figure 45A-B provides a sequence alignment of the parental 10E8.2/iMab antibody and the 10E8.4/iMab variant.

基於10E8.4/iMab抗體之有利的功能性及藥動學特性及沈澱及聚集特性之減少，進行另外的研究以評估10E8.4/iMab抗體相較於10E8.2/iMab抗體的溶解度、濁度、熱穩定性及強制降解特性。Based on the advantageous functional and pharmacokinetic properties of the 10E8.4/iMab antibody, as well as the reduction of precipitation and aggregation properties, additional studies were conducted to evaluate the solubility and turbidity of the 10E8.4/iMab antibody compared to the 10E8.2/iMab antibody. Degree, thermal stability and forced degradation characteristics.

例如，測定10E8.4/iMab抗體於4°C下的溶解度。於一組實驗中，將10E8.2/iMab及10E8.4/iMab抗體各緩衝劑交換至目標緩衝劑中並透過超離心於3000-5000g、4°C下濃縮。於不同時間點的蛋白質濃度係以於280nm的吸光度使用NanoDrop 2000分光光度計測定。所有的測量皆重複兩次，每次2.5 μL樣本，並取平均值，並接著相對於時間作圖蛋白質濃度。測定所達成的最大蛋白質濃度作為蛋白質之溶解度。如於圖39A-B中顯示的，於高於50mg/mL的濃度，10E8.4/iMab抗體在緩衝劑1（醋酸鹽緩衝劑，pH 4.5）及2（組胺酸緩衝劑，pH 5.5）中相較於10E8.2/iMab抗體一致地顯示較高的蛋白質濃度及溶解度。For example, determine the solubility of the 10E8.4/iMab antibody at 4°C. In a set of experiments, the 10E8.2/iMab and 10E8.4/iMab antibody buffers were exchanged into the target buffer and concentrated by ultracentrifugation at 3000-5000g at 4°C. The protein concentration at different time points was measured using a NanoDrop 2000 spectrophotometer with absorbance at 280 nm. All measurements were repeated twice, 2.5 μL samples each time, and the average was taken, and then the protein concentration was plotted against time. The maximum protein concentration achieved is determined as the solubility of the protein. As shown in Figure 39A-B, at a concentration higher than 50 mg/mL, the 10E8.4/iMab antibody is in buffer 1 (acetate buffer, pH 4.5) and 2 (histidine buffer, pH 5.5) Compared with the 10E8.2/iMab antibody, it consistently showed higher protein concentration and solubility.

亦分析10E8.4/iMab抗體之濁度特徵。於此分析中，將10E8.2/iMab及10E8.4/iMab抗體各自緩衝劑交換至目標緩衝劑中並透過超離心於3000-5000g、4°C下濃縮。隨時間經過使用NanoDrop 2000分光光度計測量於280 nm及350 nm的吸光度。所有的測量皆重複兩次，每次2.5 μL樣本，並取平均值，並對在超離心程序期間的類似的時間點相對於濁度（A350）作圖蛋白質濃度（A280）。如於圖40中顯示的，10E8.2/iMab及10E8.4/iMab抗體兩者之濁度皆隨時間隨著蛋白質濃度增加。特別地，於兩種所測試的緩衝劑條件，於超過100 mg/mL的相同的蛋白質濃度，10E8.2/iMab抗體相對於10E8.4/iMab顯示較高的濁度。The turbidity characteristics of the 10E8.4/iMab antibody were also analyzed. In this analysis, the buffers of the 10E8.2/iMab and 10E8.4/iMab antibodies were exchanged into the target buffer and concentrated by ultracentrifugation at 3000-5000g at 4°C. The absorbance at 280 nm and 350 nm was measured with a NanoDrop 2000 spectrophotometer over time. All measurements were repeated twice with 2.5 μL samples each time, and averaged, and the protein concentration (A280) was plotted against the turbidity (A350) at similar time points during the ultracentrifugation procedure. As shown in Figure 40, the turbidity of both 10E8.2/iMab and 10E8.4/iMab antibodies increased with time with protein concentration. In particular, under the two buffer conditions tested, the 10E8.2/iMab antibody showed higher turbidity compared to 10E8.4/iMab at the same protein concentration above 100 mg/mL.

此外，使用示差掃描量熱法（DSC）比較10E8.4/iMab抗體相對於親本10E8.2/iMab抗體的熱穩定性輪廓。DSC係一種熱分析技術，其中於樣本及參考物之溫度所需的熱增加之量之差異係以溫度之函數的形式測量。溫度記錄圖中的各峰對應於與特殊過程（諸如結晶或熔化）相關的熱效應且對分子隨溫度增加的穩定性有指示性。為測定10E8.2/iMab及10E8.4/iMab抗體之熱穩定性，使用超過濾離心裝置於4°C及3000-5000g之條件下將各個雙專一性抗體緩衝劑交換至完全相同的緩衝劑組成物中。接著將蛋白質濃度調整至~10 mg/mL並以0.22-μm過濾器無菌過濾。接著將樣本以參考緩衝劑稀釋至1 mg/mL。將參考緩衝劑（400 μL）加至96槽孔盤之編有奇數號的槽孔中並將400 μL的樣本加至相同盤子之編有偶號的槽孔中。從20 °C至90 °C以200 °C/hr的速率掃瞄盤子。以MicroCal VP-Capillary DSC自動數據分析軟體進行溫度記錄圖之分析。如於圖41中顯示的，當以DSC評估時，10E8.2/iMab及10E8.4/iMab抗體兩者皆展現類似的熱穩定性。In addition, differential scanning calorimetry (DSC) was used to compare the thermal stability profile of the 10E8.4/iMab antibody relative to the parental 10E8.2/iMab antibody. DSC is a thermal analysis technique in which the difference in the amount of heat increase required for the temperature of the sample and the reference is measured as a function of temperature. The peaks in the thermogram correspond to thermal effects associated with special processes (such as crystallization or melting) and are indicative of the stability of molecules with increasing temperature. In order to determine the thermal stability of 10E8.2/iMab and 10E8.4/iMab antibodies, an ultrafiltration centrifuge was used to exchange each bispecific antibody buffer to the same buffer at 4°C and 3000-5000g. In the composition. Then the protein concentration was adjusted to ~10 mg/mL and aseptically filtered with a 0.22-μm filter. The sample is then diluted to 1 mg/mL with reference buffer. Add the reference buffer (400 μL) to the odd-numbered wells of the 96-well plate and add 400 μL of the sample to the even-numbered wells of the same plate. Scan the tray from 20 °C to 90 °C at a rate of 200 °C/hr. Use MicroCal VP-Capillary DSC automatic data analysis software to analyze the temperature records. As shown in Figure 41, when evaluated by DSC, both the 10E8.2/iMab and 10E8.4/iMab antibodies exhibited similar thermal stability.

圖42顯示來自於10E8.2/iMab及10E8.4/iMab抗體之強制降解後的濁度分析的結果。使用超過濾離心裝置於4°C及3000-5000g的條件下將10E8.2/iMab及10E8.4/iMab抗體各自緩衝劑交換至完全相同緩衝劑組成物中。接著將蛋白質濃度調整至~10 mg/mL並以0.22-μm過濾器無菌過濾。接著將樣本培養於50 °C下以誘發強制降解，並於培養開始後第0日、第3日及第6日藉由於350 nm的吸光度測量10E8.2/iMab及10E8.4/iMab之離心前樣本及離心後樣本兩者之濁度之發展。結果顯示10E8.2/iMab抗體於所有所研究的時間點相較於10E8.4/iMab皆展現總體較高的濁度。Figure 42 shows the results of turbidity analysis after forced degradation of 10E8.2/iMab and 10E8.4/iMab antibodies. Using an ultrafiltration centrifugal device at 4°C and 3000-5000g, the buffers of the 10E8.2/iMab and 10E8.4/iMab antibodies were exchanged into exactly the same buffer composition. Then the protein concentration was adjusted to ~10 mg/mL and aseptically filtered with a 0.22-μm filter. Then the sample was cultured at 50 °C to induce forced degradation, and on the 0th, 3rd and 6th day after the start of the culture, the 10E8.2/iMab and 10E8.4/iMab were centrifuged by measuring the absorbance at 350 nm. The development of turbidity in both the pre- and post-centrifugation samples. The results showed that the 10E8.2/iMab antibody exhibited an overall higher turbidity compared to 10E8.4/iMab at all time points studied.

亦評估10E8.2/iMab及10E8.4/iMab抗體之強制降解後的分子純度。使用超過濾離心裝置於4°C及3000-5000g的條件下將10E8.2/iMab及10E8.4/iMab抗體各自緩衝劑交換至兩種緩衝劑組成物中。接著將蛋白質濃度調整至~10 mg/mL並以0.22-μm過濾器無菌過濾。接著於50°C下培養樣本以誘發強制降解，並於培養開始後第0日、第3日及第6日藉由SDS凝膠毛細管電泳在非還原條件下測定分子純度之百分比。為進行SDS凝膠毛細管電泳，藉由以20:1:0.7體積比率混合樣本緩衝劑、10% SDS及100 mM N-乙基順丁烯二醯亞胺來製備變性溶液。將二微升的樣本及7µL變性溶液充分混合，於70 °C下培養10 min並旋下。將35 µL H2 O加至樣本，接著將42 μL的混合物轉移至96槽孔盤中並於4000 rpm下離心20 min以移除氣泡。在裝載盤子後，將樣本抽吸混合，染色，分離並於充有脫染凝膠、螢光染劑及標記的Microchip中偵測。接著使用LabChip GX Reviewer分析數據以確定各樣本中完整雙專一性抗體分子相對於較小抗體片段之百分比。如於以下表6中顯示的，10E8.4/iMab抗體於所有所研究的時間點在兩種緩衝劑中相對於10E8.2/iMab抗體皆顯示較好的完整分子純度： 表6.

Figure 107146176-A0304-0006
The molecular purity of 10E8.2/iMab and 10E8.4/iMab antibodies after forced degradation was also evaluated. The 10E8.2/iMab and 10E8.4/iMab antibody buffers were exchanged into two buffer compositions using an ultrafiltration centrifugal device under the conditions of 4°C and 3000-5000g. Then the protein concentration was adjusted to ~10 mg/mL and aseptically filtered with a 0.22-μm filter. The samples were then incubated at 50°C to induce forced degradation, and the percentage of molecular purity was determined by SDS gel capillary electrophoresis under non-reducing conditions on the 0th, 3rd, and 6th days after the start of the culture. To perform SDS gel capillary electrophoresis, a denaturing solution was prepared by mixing sample buffer, 10% SDS, and 100 mM N-ethylmaleimide in a volume ratio of 20:1:0.7. Mix two microliters of sample and 7µL of denaturation solution thoroughly, incubate at 70 °C for 10 min and spin off. Add 35 μL of H 2 O to the sample, then transfer 42 μL of the mixture to a 96-well plate and centrifuge at 4000 rpm for 20 min to remove air bubbles. After loading the plate, the sample is aspirated, mixed, stained, separated, and detected in Microchip filled with a de-staining gel, fluorescent dye, and label. Then use LabChip GX Reviewer to analyze the data to determine the percentage of intact bispecific antibody molecules relative to smaller antibody fragments in each sample. As shown in Table 6 below, the 10E8.4/iMab antibody showed better complete molecular purity than the 10E8.2/iMab antibody in both buffers at all time points studied: Table 6.
Figure 107146176-A0304-0006

亦進行聚集分析。具體言之，使用超過濾離心裝置在4°C及3000-5000g的條件下將10E8.2/iMab及10E8.4/iMab抗體各自緩衝劑交換至兩種緩衝劑組成物中。接著將蛋白質濃度調整至~10 mg/mL並以0.22-μm過濾器無菌過濾。接著於50 °C下培養樣本以誘發強制降解，並以SE-HPLC（粒徑篩析層析法）測定各蛋白質樣本中的高分子量（HMW）部分作為聚集之測量結果。粒徑篩析層析法係使用Agilent 1260 Infinity系統及TSKGel G3000SWXL管柱（300×7.8 mm，5μm）進行。移動相係50mM PB，300 mM NaCl，pH 7.0±0.2並將流率設為1.0 mL/min。將樣本離心（於4 °C下~10000 rpm共2 min），注射並於280 nm下偵測以測定樣本中的HMW之百分比。如於以下表7顯示的，雖然10E8.4/iMab抗體於T0時具有較大的HMW量，其相較於10E8.2/iMab在於強制降解誘發性條件下培養期間顯示較慢的隨時間HMW百分比改變。 表7.

Figure 107146176-A0304-0007
Aggregation analysis was also performed. Specifically, the 10E8.2/iMab and 10E8.4/iMab antibody buffers were exchanged into two buffer compositions using an ultrafiltration centrifugal device at 4°C and 3000-5000 g. Then the protein concentration was adjusted to ~10 mg/mL and aseptically filtered with a 0.22-μm filter. The samples were then incubated at 50 °C to induce forced degradation, and the high molecular weight (HMW) fraction of each protein sample was determined by SE-HPLC (particle size analysis chromatography) as a measurement result of aggregation. The particle size sieve analysis chromatography was performed using Agilent 1260 Infinity system and TSKGel G3000SWXL column (300×7.8 mm, 5μm). The mobile phase is 50 mM PB, 300 mM NaCl, pH 7.0 ± 0.2 and the flow rate is set to 1.0 mL/min. Centrifuge the sample (2 min at 4 °C ~ 10000 rpm), inject and detect at 280 nm to determine the percentage of HMW in the sample. As shown in Table 7 below, although the 10E8.4/iMab antibody has a larger amount of HMW at T0, compared to 10E8.2/iMab, it exhibits slower HMW over time during culture under forced degradation-inducing conditions. The percentage change. Table 7.
Figure 107146176-A0304-0007

此外，如於圖43中顯示的，試管內比較10E8.2/iMab及10E8.4/iMab抗體之功能活性。具體言之，病毒中和係以單一輪檢定使用TZM-bl細胞及代表各種演化支及來源的118種HIV-1第2級HIV-1 Env假病毒如先前描述地（Seaman等人2010. J. Virol. 84, 1439-1452）評估。結果顯示除了其於溶解度的改善、於濁度的減低及在熱壓力誘發性條件下於生物生物物理特性的改善外，10E8.4/iMab抗體相較於10E8.2/iMab於對抗一大組HIV-1 Env假型化病毒的中和活性方面亦展現大約2.5倍增強。In addition, as shown in Figure 43, the functional activities of the 10E8.2/iMab and 10E8.4/iMab antibodies were compared in the test tube. Specifically, the virus neutralization system uses TZM-bl cells and 118 HIV-1 level 2 HIV-1 Env pseudoviruses representing various evolutionary branches and sources in a single round of assays as previously described (Seaman et al. 2010. J Virol. 84, 1439-1452) evaluation. The results showed that, in addition to its improved solubility, reduced turbidity, and improved biophysical properties under thermal stress-induced conditions, the 10E8.4/iMab antibody was more effective against a large group than 10E8.2/iMab. The neutralizing activity of HIV-1 Env pseudotyped virus also exhibited an approximately 2.5-fold enhancement.

亦活體內比較10E8.2/iMab及10E8.4/iMab抗體之功能活性。免疫缺陷型NSG小鼠（NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ）在開始抗體治療前係以人類造血幹細胞重建並以第2級演化支B HIV-1JR-CSF 感染四週。接著將小鼠每週以允許其等於人類化小鼠中的評估的10E8.2/iMab或10E8.4/iMab之經修改的變體治療。如於圖44中顯示的，於以10E8.2/iMab治療小鼠中觀察到~1.7 log的最大平均病毒負載減低，且於以10E8.4/iMab治療小鼠中觀察到~2.4 log的最大平均病毒負載減低」。The functional activities of 10E8.2/iMab and 10E8.4/iMab antibodies were also compared in vivo. NSG immunodeficient mice (NOD.Cg- Prkdc scid Il2rg tm1Wjl / SzJ ) based reconstruction to human hematopoietic stem cells and to the second stage clade B HIV-1 JR-CSF infection prior to antibody treatment started four weeks. The mice were then treated weekly with modified variants of 10E8.2/iMab or 10E8.4/iMab that allowed them to be equal to the evaluated in humanized mice. As shown in Figure 44, a maximum mean viral load reduction of ~1.7 log was observed in mice treated with 10E8.2/iMab, and a maximum of ~2.4 log was observed in mice treated with 10E8.4/iMab The average virus load is reduced.”

於本文中使用的術語及表現方式係用作為用於描述的術語及表現方式且非作為限制，且於使用如此術語及表現方式時並非意欲排除所顯示及描述的特徵或其等之部分之任何相等事物。此外，於已描述本發明之某些實施方式後，對所屬技術領域中具有通常知識者而言以下會是明顯的：可使用併入本發明之概念的其他實施方式而不會偏離本發明之精神及範圍。因此，所描述實施方式於所有方面皆應被視為僅係闡明性的且非限制性的。The terms and expressions used in this article are used as descriptive terms and expressions and not as limitations, and the use of such terms and expressions is not intended to exclude any of the displayed and described features or parts thereof Equal things. In addition, after certain embodiments of the present invention have been described, it will be obvious to those having ordinary knowledge in the art that other embodiments incorporating the concept of the present invention can be used without departing from the concept of the present invention. Spirit and scope. Therefore, the described embodiments should be regarded as merely illustrative and non-limiting in all respects.

無without

於圖式中，相同的符號一般於不同觀點表示相同的部分。此外，該等圖式並不一定按比例，而是一般給出強調之處以闡明本發明之原則。於以下描述中，各種本發明之實施方式係參照以下圖式描述，其中：In the drawings, the same symbols generally represent the same parts from different viewpoints. In addition, the drawings are not necessarily to scale, but are generally emphasized to clarify the principles of the present invention. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:

圖1係闡明得自兩種IgG單株抗體的CrossMab抗體的圖。Figure 1 is a diagram illustrating CrossMab antibodies derived from two IgG monoclonal antibodies.

圖2A係闡明靶向CD4的iMab抗體（單株抗體ibalizumab之簡寫）及靶向CCR5的Pro 140抗體的圖。Figure 2A is a diagram illustrating the iMab antibody targeting CD4 (abbreviation of the monoclonal antibody ibalizumab) and the Pro 140 antibody targeting CCR5.

圖2B係闡明靶向HIV套膜gp120的mAb的圖。Figure 2B is a diagram illustrating mAb targeting HIV mantle gp120.

圖3係比較使用iMab及10E8抗體之組合及CrossMab雙專一性10E8/iMab抗體對抗細胞至細胞HIV傳播的最大抑制百分比（MPI）的圖。除非另外指出，所有的基於iMab的雙專一性抗體皆使用MV1變體構築。Figure 3 is a graph comparing the maximum inhibition percentage (MPI) of the combination of iMab and 10E8 antibody and CrossMab dual specific 10E8/iMab antibody against cell-to-cell HIV transmission. Unless otherwise indicated, all iMab-based bispecific antibodies are constructed using MV1 variants.

圖4A-J係一系列比較使用不同濃度的10E8、Pro 140或10E8/P140抗體的X4及雙向性HIV之各種病毒株之抑制的圖。P140係Pro 140之簡寫。Figures 4A-J are a series of graphs comparing the inhibition of various strains of X4 and bidirectional HIV using different concentrations of 10E8, Pro 140 or 10E8/P140 antibodies. P140 is short for Pro 140.

圖5A-G係一系列比較使用不同濃度的10E8、Pro 140、10E8/P140或個別10E8及Pro 140單株抗體之組合的HIV之各種病毒株之抑制的圖。Figures 5A-G are a series of graphs comparing the inhibition of various strains of HIV using different concentrations of 10E8, Pro 140, 10E8/P140 or a combination of individual 10E8 and Pro 140 monoclonal antibodies.

圖6A-D係一系列比較使用不同濃度的10E8、X19、10E8/X19或10E8/P140抗體的HIV之各種病毒株之抑制的圖。Figures 6A-D are a series of graphs comparing the inhibition of various strains of HIV using different concentrations of 10E8, X19, 10E8/X19 or 10E8/P140 antibodies.

圖7A-H係一系列比較使用不同濃度的10E8、Pro 140、10E8/P140及10E8/αHer2抗體的HIV之各種病毒株之抑制的圖。Figure 7A-H is a series of graphs comparing the inhibition of various strains of HIV using different concentrations of 10E8, Pro 140, 10E8/P140 and 10E8/αHer2 antibodies.

圖8A係比較CrossMab雙專一性抗體10E8/iMab及Δ10E8/iMab與HIV-1醣蛋白MPER的結合的圖。Figure 8A is a graph comparing the binding of CrossMab bispecific antibodies 10E8/iMab and Δ10E8/iMab to HIV-1 glycoprotein MPER.

圖8B-E係一系列比較10E8（淺灰色線）及Δ10E8（深灰色線）對抗iMab抗性R5病毒（圖8B）及X4病毒（圖8C）的抑制百分比、以及10E8/iMab（淺灰色線）及Δ10E8/iMab（深灰色線）對抗iMab抗性R5病毒（圖8D）及X4病毒（圖8E）的抑制百分比的圖。Figure 8B-E is a series of comparisons of the inhibition percentages of 10E8 (light gray line) and Δ10E8 (dark gray line) against iMab resistant R5 virus (Figure 8B) and X4 virus (Figure 8C), and 10E8/iMab (light gray line) ) And Δ10E8/iMab (dark gray line) against iMab resistant R5 virus (Figure 8D) and X4 virus (Figure 8E) inhibition percentage graph.

圖9A-G係一系列比較使用不同濃度的10E8、Δ10E8、4E10、10E8/P140、Δ10E8/P140及4E10/P140抗體的HIV之各種病毒株之抑制的圖。Figures 9A-G are a series of graphs comparing the inhibition of various strains of HIV using different concentrations of 10E8, Δ10E8, 4E10, 10E8/P140, Δ10E8/P140, and 4E10/P140 antibodies.

圖10係比較CrossMab抗體10E8/Pro140及10E8/iMab、其等之親本單株抗體10E8、Pro140及iMab、及各種其他靶向HIV套膜的單株抗體對抗一大組的HIV套膜假型化（pseudotyped）病毒的抗病毒涵蓋範圍的圖。Figure 10 compares CrossMab antibodies 10E8/Pro140 and 10E8/iMab, their parental monoclonal antibodies 10E8, Pro140 and iMab, and various other monoclonal antibodies targeting HIV mantle against a large group of HIV mantle pseudotypes A diagram of the anti-virus coverage of pseudotyped viruses.

圖11A-E係一系列比較使用單株抗體iMab（在所有小圖中皆為灰色紋路）及CrossMab抗體PGT145/ibalizumab（145/iMab；圖11A）、PGT128/ibalizumab（128/iMab；圖11B）、PGT151/ibalizumab（151/iMab；圖11C）、3BNC117/ibalizumab（117/iMab；圖11D）及10E8/ibalizumab（10E8/iMab；圖11E）的一大組的HIV套膜假型化病毒之最大抑制百分比（MPI）的圖。Figure 11A-E is a series of comparisons using monoclonal antibody iMab (grey lines in all the small images) and CrossMab antibody PGT145/ibalizumab (145/iMab; Figure 11A), PGT128/ibalizumab (128/iMab; Figure 11B) , PGT151/ibalizumab (151/iMab; Figure 11C), 3BNC117/ibalizumab (117/iMab; Figure 11D) and 10E8/ibalizumab (10E8/iMab; Figure 11E) are the largest group of HIV pseudotyped viruses Graph of percent inhibition (MPI).

圖12A-E係一系列比較CrossMab抗體PGT145/ibalizumab（145/iMab；圖12A）、PGT128/ibalizumab（128/iMab；圖12B）、PGT151/ibalizumab（151/iMab；圖12C）、3BNC117/ibalizumab（117/iMab；圖12D）及10E8/ibalizumab（10E8/iMab；圖12E）對抗一大組的HIV套膜假型化病毒之最大抑制百分比（MPI）及IC80抗體濃度的圖。Figure 12A-E is a series of comparative CrossMab antibodies PGT145/ibalizumab (145/iMab; Figure 12A), PGT128/ibalizumab (128/iMab; Figure 12B), PGT151/ibalizumab (151/iMab; Figure 12C), 3BNC117/ibalizumab ( 117/iMab; Figure 12D) and 10E8/ibalizumab (10E8/iMab; Figure 12E) against a large group of HIV envelope pseudotyped virus maximum inhibition percentage (MPI) and IC80 antibody concentration graphs.

圖13A-E係一系列對於基於iMab及基於Pro140的CrossMab雙專一性抗體及其等之親本抗體對於PGT145/iMab及PGT145/Pro140（圖13A）、3BNC117/iMab及3BNC117/Pro140（圖13B）、PGT128/iMab及PGT128/Pro140（圖13C）、PGT151/iMab及PGT151/Pro140（圖13D）及10E8/iMab及10E8/Pro140（圖13E）比較IC80抗體濃度的圖。Figure 13A-E is a series of iMab and Pro140-based CrossMab bispecific antibodies and their parental antibodies against PGT145/iMab and PGT145/Pro140 (Figure 13A), 3BNC117/iMab and 3BNC117/Pro140 (Figure 13B) , PGT128/iMab and PGT128/Pro140 (Figure 13C), PGT151/iMab and PGT151/Pro140 (Figure 13D) and 10E8/iMab and 10E8/Pro140 (Figure 13E) to compare the concentration of IC80 antibody.

圖14A-E係一系列對於基於iMab及基於Pro140的CrossMab雙專一性抗體及其等之親本抗體對於PGT145/iMab及PGT145/Pro140（圖14A）、3BNC117/iMab及3BNC117/Pro140（圖14B）、PGT128/iMab及PGT128/Pro140（圖14C）、PGT151/iMab及PGT151/Pro140（圖14D）及10E8/iMab及10E8/Pro140（圖14E）比較IC50抗體濃度的圖。Figure 14A-E is a series of iMab and Pro140-based CrossMab bispecific antibodies and their parental antibodies against PGT145/iMab and PGT145/Pro140 (Figure 14A), 3BNC117/iMab and 3BNC117/Pro140 (Figure 14B) , PGT128/iMab and PGT128/Pro140 (Figure 14C), PGT151/iMab and PGT151/Pro140 (Figure 14D) and 10E8/iMab and 10E8/Pro140 (Figure 14E) comparing IC50 antibody concentrations.

圖15A-E係對於基於iMab的CrossMab雙專一性抗體及其等之親本抗體對抗HIV之細胞至細胞傳播對於10E8/iMab（圖15A）、3BNC117/iMab（圖15B）、PGT145/iMab（圖15C）、PGT128/iMab（圖15D）及PGT151/iMab（圖15E）展示IC80抗體濃度的圖。Figure 15A-E shows the cell-to-cell spread of iMab-based CrossMab bispecific antibodies and their parent antibodies against HIV. For 10E8/iMab (Figure 15A), 3BNC117/iMab (Figure 15B), PGT145/iMab (Figure 15A) 15C), PGT128/iMab (Figure 15D) and PGT151/iMab (Figure 15E) show graphs of IC80 antibody concentration.

圖16係展示CrossMab雙專一性抗體及親本抗體對抗HIV之細胞至細胞傳播的最大抑制百分比（MPI）的圖。Figure 16 is a graph showing the maximum percentage inhibition (MPI) of the CrossMab bispecific antibody and the parent antibody against HIV cell-to-cell transmission.

圖17A係對於不同濃度的10E8、Pro 140、10E8/P140 CrossMab雙專一性抗體、及個別的10E8及Pro 140單株抗體之組合比較HIV病毒株之抑制的圖。Figure 17A is a graph comparing the inhibition of HIV strains with different concentrations of 10E8, Pro 140, 10E8/P140 CrossMab bispecific antibodies, and individual combinations of 10E8 and Pro 140 monoclonal antibodies.

圖17B係對於不同濃度的iMab、10E8、10E8/iMab CrossMab雙專一性抗體、及個別的10E8及iMab單株抗體之組合比較HIV病毒株抑制的圖。Figure 17B is a graph comparing the inhibition of HIV strains with different concentrations of iMab, 10E8, 10E8/iMab CrossMab bispecific antibodies, and individual combinations of 10E8 and iMab monoclonal antibodies.

圖18A-D係一系列對於不同濃度的10E8、Pro140、10E8/P140及10E8/515H7抗體比較各種HIV R5病毒株之抑制的圖。Figure 18A-D is a series of graphs comparing the inhibition of various HIV R5 virus strains with different concentrations of 10E8, Pro140, 10E8/P140 and 10E8/515H7 antibodies.

圖18E-H係一系列對於各種濃度的10E8、515H7及10E8/515H7抗體比較各種HIV X4病毒株之抑制的圖。Figure 18E-H is a series of graphs comparing the inhibition of various HIV X4 virus strains with various concentrations of 10E8, 515H7 and 10E8/515H7 antibodies.

圖19A-B係一系列對於不同濃度的10E8/Pro140、10E8/iMab、10E8/515H7及10E8/X19抗體比較各種HIV病毒株之抑制的圖。Figure 19A-B is a series of graphs comparing the inhibition of various HIV strains with different concentrations of 10E8/Pro140, 10E8/iMab, 10E8/515H7 and 10E8/X19 antibodies.

圖19C顯示在TZM-bl細胞上存在的CD4、CCR5及CXCR4受體之密度。Figure 19C shows the density of CD4, CCR5 and CXCR4 receptors present on TZM-bl cells.

圖20比較CrossMab雙專一性抗體10E8/Pro140、Δ10E8/Pro140及4E10/Pro140與HIV-1醣蛋白MPER的結合。Figure 20 compares the binding of CrossMab bispecific antibodies 10E8/Pro140, Δ10E8/Pro140, and 4E10/Pro140 to HIV-1 glycoprotein MPER.

圖21A-G係一系列對於不同濃度的4E10、Pro140及4E10/P140及10E8/P140抗體比較HIV之各種病毒株之抑制的圖。Figure 21A-G is a series of graphs comparing the inhibition of various HIV strains with different concentrations of 4E10, Pro140, 4E10/P140 and 10E8/P140 antibodies.

圖22A係CrossMab抗體10E8/iMab、10E8/P140及3BNC117/iMab之粒徑篩析層析法分析。Figure 22A is the particle size sieve chromatography analysis of CrossMab antibodies 10E8/iMab, 10E8/P140 and 3BNC117/iMab.

圖22B係單株抗體iMab、10E8及Pro140之粒徑篩析層析法分析。Figure 22B is the particle size sieving chromatography analysis of monoclonal antibodies iMab, 10E8 and Pro140.

圖23係單株抗體10E8及由與4E10輕鏈配對的10E8重鏈構成的嵌合抗體之粒徑篩析層析法分析。Figure 23 is a particle size chromatographic analysis of the monoclonal antibody 10E8 and the chimeric antibody composed of the 10E8 heavy chain paired with the 4E10 light chain.

圖24A-C係一系列的以下者之粒徑篩析層析法圖：單株抗體10E8及4E10及由與4E10輕鏈配對的10E8重鏈構成的嵌合抗體（圖24A）、單株抗體10E8及具有於10E8輕鏈中經基因工程設計的可能穩定化突變的10E8突變體（圖24B）、及單株抗體10E8及以非10E8抗體之κ輕鏈基因嫁接的10E8突變體（圖24C）。Figure 24A-C is a series of particle size screening chromatographic diagrams of the following: monoclonal antibodies 10E8 and 4E10 and chimeric antibodies composed of 10E8 heavy chains paired with 4E10 light chains (Figure 24A), monoclonal antibodies 10E8 and 10E8 mutants with possible stabilizing mutations genetically engineered in the 10E8 light chain (Figure 24B), and monoclonal antibodies 10E8 and 10E8 mutants grafted with κ light chain genes other than 10E8 antibodies (Figure 24C) .

圖25係單株抗體4E10及以包括CDR1區、CDR2區、CDR3區、或組合的CDR1、CDR2及CDR3區的10E8之輕區域基因嫁接的4E10突變體之粒徑篩析層析法圖。Fig. 25 is a particle size screening chromatogram of 4E10 mutants of monoclonal antibody 4E10 and 4E10 mutant grafted with light region genes of 10E8 including CDR1, CDR2, CDR3, or a combination of CDR1, CDR2, and CDR3.

圖26A係10E8嵌合抗體之粒徑篩析層析法圖。CDR123係與以10E8抗體生殖細胞系CDR區序列基因嫁接的10E8輕鏈配對的10E8重鏈之嵌合抗體。FW123係與以10E8抗體生殖細胞系骨架區序列基因嫁接的10E8輕鏈配對的10E8重鏈之嵌合抗體。Figure 26A is a chromatogram of particle size analysis of 10E8 chimeric antibody. CDR123 is a chimeric antibody of 10E8 heavy chain paired with 10E8 light chain genetically grafted with 10E8 antibody germ cell CDR region sequence. FW123 is a chimeric antibody of 10E8 heavy chain paired with 10E8 light chain genetically grafted with 10E8 antibody germ cell line skeleton region sequence.

圖26B係顯示CDR123及FW123抗體之表現、HIV MPER結合能力、粒徑篩析層析法輪廓、及HIV中和輪廓的表格。Figure 26B is a table showing the performance of CDR123 and FW123 antibodies, HIV MPER binding capacity, particle size screening chromatography profile, and HIV neutralization profile.

圖27係單株抗體10E8、其體細胞變體H6L10、及由與Pro140配對的H6L10組成的CrossMab雙專一性抗體之粒徑篩析層析法圖。Figure 27 is a particle size chromatogram of the monoclonal antibody 10E8, its somatic variant H6L10, and the CrossMab bispecific antibody composed of H6L10 paired with Pro140.

圖28係描繪小鼠模型中10E8、H6L10/Pro 140及其親本抗體之藥動學輪廓的圖。Figure 28 is a graph depicting the pharmacokinetic profile of 10E8, H6L10/Pro 140 and their parent antibodies in a mouse model.

圖29係比較10E8v 1.0/iMab或P140 CrossMab抗體與10E8/iMab或P140抗體之效力的圖。Figure 29 is a graph comparing the efficacy of 10E8v 1.0/iMab or P140 CrossMab antibody and 10E8/iMab or P140 antibody.

圖30係描繪小鼠模型中10E8及得自數種10E8變體及iMab或P140的CrossMab抗體之藥動學的圖。Figure 30 is a graph depicting the pharmacokinetics of 10E8 and CrossMab antibodies derived from several 10E8 variants and iMab or P140 in a mouse model.

圖31A-B係一系列描繪10E8v1.1 /P140及10E8v2.0 /iMab抗體之HIV病毒涵蓋範圍的圖。Figures 31A-B are a series of graphs depicting the HIV virus coverage of 10E8 v1.1 /P140 and 10E8 v2.0/iMab antibodies.

圖31C-D係一系列描繪10E8v1.1 /P140及10E8v2.0 /iMab抗體之粒徑篩析層析法穩定性圖的圖。Figure 31C-D is a series of graphs depicting the stability of 10E8 v1.1 /P140 and 10E8 v2.0 /iMab antibodies by size screening chromatography.

圖32A-B係一系列描繪於4°C下儲存在PBS中的10E8v1.1 /P140及10E8v2.0 /iMab抗體之粒徑篩析穩定性圖的圖。Figure 32A-B is a series of graphs depicting the particle size sieve stability graphs of 10E8 v1.1 /P140 and 10E8 v2.0/iMab antibodies stored in PBS at 4°C.

圖33描繪10E8v2.0 /iMab (N297A）抗體之天然質量光譜學分析。Figure 33 depicts the natural mass spectroscopy analysis of the 10E8 v2.0 /iMab (N297A) antibody.

圖34A-C係一系列比較10E8v1.1 /P140及10E8v2.0 /iMab對HIV Clade C組之活性、及該等抗體之IC50及IC80活性的圖。Figure 34A-C is a series of graphs comparing the activities of 10E8 v1.1 /P140 and 10E8 v2.0 /iMab on HIV Clade C group, and the IC50 and IC80 activities of these antibodies.

圖35及36係比較10E8v1.1 /P140、10E8v2.0 /iMab、及各種單株抗體對抗HIV的效力的圖。Figures 35 and 36 are graphs comparing the efficacy of 10E8 v1.1 /P140, 10E8 v2.0 /iMab, and various monoclonal antibodies against HIV.

圖37A-C展示所選數目的10E8V2.0 /iMab（亦稱為10E8.2/iMab）變體維持功能性抗病毒活性及增加的溶解度。圖37A展示10E8.2/iMab變體中的一些於試管內HIV-1中和檢定中維持功能活性。圖37B顯示10E8.2/iMab及10E8.2/iMab變體中的一些具有類似的活體內藥動學輪廓。圖37C顯示10E8.2/iMab及10E8.2/iMab變體中的一些於熱壓力誘發性條件下的沈澱輪廓。Figures 37A-C show that a selected number of 10E8 V2.0 /iMab (also known as 10E8.2/iMab) variants maintain functional antiviral activity and increased solubility. Figure 37A shows that some of the 10E8.2/iMab variants maintain functional activity in the in vitro HIV-1 neutralization assay. Figure 37B shows that some of the 10E8.2/iMab and 10E8.2/iMab variants have similar in vivo pharmacokinetic profiles. Figure 37C shows the precipitation profile of some of the 10E8.2/iMab and 10E8.2/iMab variants under thermal pressure-induced conditions.

圖38A-B顯示粒徑篩析層析法之結果，其被用於鑑認於熱壓力誘發性條件後聚集最少的10E8.2/iMab變體。Figures 38A-B show the results of particle size sieve analysis chromatography, which was used to identify the 10E8.2/iMab variant that aggregated the least after thermal pressure-induced conditions.

圖39A-B闡明於超離心後於4°C下10E8.2/iMab及10E8.4/iMab變體之溶解度。Figures 39A-B illustrate the solubility of 10E8.2/iMab and 10E8.4/iMab variants at 4°C after ultracentrifugation.

圖40展示不同濃度的10E8.2/iMab及10E8.4/iMab變體隨時間經過的濁度。Figure 40 shows the turbidity of 10E8.2/iMab and 10E8.4/iMab variants at different concentrations over time.

圖41顯示以示差掃描量熱法評估的10E8.2/iMab及10E8.4/iMab變體之熱穩定性。Figure 41 shows the thermal stability of 10E8.2/iMab and 10E8.4/iMab variants evaluated by differential scanning calorimetry.

圖42展示10E8.2/iMab及10E8.4/iMab變體在於50°C下強制降解六日後的濁度。對每一組直方圖而言，自左至右的長條代表10E8.2/iMab（離心前）、10E8.4/iMab（離心前）、10E8.2/iMab（離心後）、及10E8.4/iMab（離心後）。Figure 42 shows the turbidity of the 10E8.2/iMab and 10E8.4/iMab variants after six days of forced degradation at 50°C. For each group of histograms, the long bars from left to right represent 10E8.2/iMab (before centrifugation), 10E8.4/iMab (before centrifugation), 10E8.2/iMab (after centrifugation), and 10E8. 4/iMab (after centrifugation).

圖43顯示10E8.2/iMab及10E8.4/iMab變體之抗HIV涵蓋範圍。Figure 43 shows the anti-HIV coverage of 10E8.2/iMab and 10E8.4/iMab variants.

圖44係顯示10E8.2/iMab及10E8.4/iMab變體在HIV-1感染之人類化小鼠模型的活體中的抗病毒活性的圖。Figure 44 is a graph showing the antiviral activity of 10E8.2/iMab and 10E8.4/iMab variants in vivo in a humanized mouse model of HIV-1 infection.

圖45A顯示10E8.2/iMab之輕鏈（SEQ ID NO:33）及10E8.4/iMab變體之輕鏈（SEQ ID NO:44）之序列排比。Figure 45A shows the sequence alignment of the light chain of 10E8.2/iMab (SEQ ID NO: 33) and the light chain of 10E8.4/iMab variant (SEQ ID NO: 44).

圖45B顯示10E8.2/iMab之重鏈（SEQ ID NO:34）及10E8.4/iMab變體之重鏈（SEQ ID NO:42）之序列排比。加底線的序列代表CDR1、CDR2、及CDR3。斜體字的序列代表恆定輕鏈或恆定重鏈序列。Figure 45B shows the sequence alignment of the heavy chain of 10E8.2/iMab (SEQ ID NO: 34) and the heavy chain of 10E8.4/iMab variant (SEQ ID NO: 42). The underlined sequences represent CDR1, CDR2, and CDR3. The sequences in italics represent constant light chain or constant heavy chain sequences.

圖46係顯示為穩定的且同時維持抗HIV活性的10E8抗體之例示性變體的圖。Figure 46 is a graph showing an exemplary variant of the 10E8 antibody that is stable while maintaining anti-HIV activity.

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<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 8

Figure 107146176-A0305-02-0106-20
Figure 107146176-A0305-02-0107-21
Figure 107146176-A0305-02-0108-22
<400> 8
Figure 107146176-A0305-02-0106-20
Figure 107146176-A0305-02-0107-21
Figure 107146176-A0305-02-0108-22

<210> 9 <210> 9

<211> 214 <211> 214

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 9

Figure 107146176-A0305-02-0109-23
Figure 107146176-A0305-02-0110-24
<400> 9
Figure 107146176-A0305-02-0109-23
Figure 107146176-A0305-02-0110-24

<210> 10 <210> 10

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 10

Figure 107146176-A0305-02-0110-25
Figure 107146176-A0305-02-0111-26
Figure 107146176-A0305-02-0112-27
<400> 10
Figure 107146176-A0305-02-0110-25
Figure 107146176-A0305-02-0111-26
Figure 107146176-A0305-02-0112-27

<210> 11 <210> 11

<211> 217 <211> 217

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 11

Figure 107146176-A0305-02-0112-28
Figure 107146176-A0305-02-0113-29
<400> 11
Figure 107146176-A0305-02-0112-28
Figure 107146176-A0305-02-0113-29

210> 12 210> 12

<211> 456 <211> 456

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 12

Figure 107146176-A0305-02-0114-30
Figure 107146176-A0305-02-0115-31
Figure 107146176-A0305-02-0116-32
<400> 12
Figure 107146176-A0305-02-0114-30
Figure 107146176-A0305-02-0115-31
Figure 107146176-A0305-02-0116-32

<210> 13 <210> 13

<211> 212 <211> 212

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 13

Figure 107146176-A0305-02-0116-33
Figure 107146176-A0305-02-0117-34
<400> 13
Figure 107146176-A0305-02-0116-33
Figure 107146176-A0305-02-0117-34

<210> 14 <210> 14

<211> 454 <211> 454

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 14

Figure 107146176-A0305-02-0118-35
Figure 107146176-A0305-02-0119-36
Figure 107146176-A0305-02-0120-37
<400> 14
Figure 107146176-A0305-02-0118-35
Figure 107146176-A0305-02-0119-36
Figure 107146176-A0305-02-0120-37

<210> 15 <210> 15

<211> 214 <211> 214

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 15

Figure 107146176-A0305-02-0120-38
Figure 107146176-A0305-02-0121-39
<400> 15
Figure 107146176-A0305-02-0120-38
Figure 107146176-A0305-02-0121-39

<210> 16 <210> 16

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 16

Figure 107146176-A0305-02-0121-40
Figure 107146176-A0305-02-0122-41
Figure 107146176-A0305-02-0123-42
Figure 107146176-A0305-02-0124-43
<400> 16
Figure 107146176-A0305-02-0121-40
Figure 107146176-A0305-02-0122-41
Figure 107146176-A0305-02-0123-42
Figure 107146176-A0305-02-0124-43

<210> 17 <210> 17

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 17

Figure 107146176-A0305-02-0124-44
Figure 107146176-A0305-02-0125-45
<400> 17
Figure 107146176-A0305-02-0124-44
Figure 107146176-A0305-02-0125-45

<210> 18 <210> 18

<211> 457 <211> 457

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 18

Figure 107146176-A0305-02-0125-46
Figure 107146176-A0305-02-0126-47
Figure 107146176-A0305-02-0127-48
Figure 107146176-A0305-02-0128-49
<400> 18
Figure 107146176-A0305-02-0125-46
Figure 107146176-A0305-02-0126-47
Figure 107146176-A0305-02-0127-48
Figure 107146176-A0305-02-0128-49

<210> 19 <210> 19

<211> 212 <211> 212

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 19

Figure 107146176-A0305-02-0128-50
Figure 107146176-A0305-02-0129-51
<400> 19
Figure 107146176-A0305-02-0128-50
Figure 107146176-A0305-02-0129-51

<210> 20 <210> 20

<211> 455 <211> 455

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 20

Figure 107146176-A0305-02-0129-52
Figure 107146176-A0305-02-0130-53
Figure 107146176-A0305-02-0131-54
<400> 20
Figure 107146176-A0305-02-0129-52
Figure 107146176-A0305-02-0130-53
Figure 107146176-A0305-02-0131-54

<210> 21 <210> 21

<211> 213 <211> 213

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 21

Figure 107146176-A0305-02-0132-55
Figure 107146176-A0305-02-0133-56
<400> 21
Figure 107146176-A0305-02-0132-55
Figure 107146176-A0305-02-0133-56

<210> 22 <210> 22

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 22

Figure 107146176-A0305-02-0133-57
Figure 107146176-A0305-02-0134-58
Figure 107146176-A0305-02-0135-59
<400> 22
Figure 107146176-A0305-02-0133-57
Figure 107146176-A0305-02-0134-58
Figure 107146176-A0305-02-0135-59

<210> 23 <210> 23

<211> 219 <211> 219

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 23

Figure 107146176-A0305-02-0135-60
Figure 107146176-A0305-02-0136-61
Figure 107146176-A0305-02-0137-62
<400> 23
Figure 107146176-A0305-02-0135-60
Figure 107146176-A0305-02-0136-61
Figure 107146176-A0305-02-0137-62

<210> 24 <210> 24

<211> 465 <211> 465

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 24

Figure 107146176-A0305-02-0137-63
Figure 107146176-A0305-02-0138-64
Figure 107146176-A0305-02-0139-65
<400> 24
Figure 107146176-A0305-02-0137-63
Figure 107146176-A0305-02-0138-64
Figure 107146176-A0305-02-0139-65

<210> 25 <210> 25

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 25

Figure 107146176-A0305-02-0139-66
Figure 107146176-A0305-02-0140-67
<400> 25
Figure 107146176-A0305-02-0139-66
Figure 107146176-A0305-02-0140-67

<210> 26 <210> 26

<211> 454 <211> 454

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 26

Figure 107146176-A0305-02-0141-68
Figure 107146176-A0305-02-0142-69
Figure 107146176-A0305-02-0143-70
<400> 26
Figure 107146176-A0305-02-0141-68
Figure 107146176-A0305-02-0142-69
Figure 107146176-A0305-02-0143-70

<210> 27 <210> 27

<211> 214 <211> 214

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 27

Figure 107146176-A0305-02-0143-71
Figure 107146176-A0305-02-0144-72
<400> 27
Figure 107146176-A0305-02-0143-71
Figure 107146176-A0305-02-0144-72

<210> 28 <210> 28

<211> 214 <211> 214

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 28

Figure 107146176-A0305-02-0145-73
Figure 107146176-A0305-02-0146-74
<400> 28
Figure 107146176-A0305-02-0145-73
Figure 107146176-A0305-02-0146-74

<210> 29 <210> 29

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 29

Figure 107146176-A0305-02-0146-75
Figure 107146176-A0305-02-0147-76
<400> 29
Figure 107146176-A0305-02-0146-75
Figure 107146176-A0305-02-0147-76

<210> 30 <210> 30

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 30

Figure 107146176-A0305-02-0147-77
Figure 107146176-A0305-02-0148-78
Figure 107146176-A0305-02-0149-79
<400> 30
Figure 107146176-A0305-02-0147-77
Figure 107146176-A0305-02-0148-78
Figure 107146176-A0305-02-0149-79

<210> 31 <210> 31

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 31

Figure 107146176-A0305-02-0150-80
Figure 107146176-A0305-02-0151-81
<400> 31
Figure 107146176-A0305-02-0150-80
Figure 107146176-A0305-02-0151-81

<210> 32 <210> 32

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 32

Figure 107146176-A0305-02-0151-82
Figure 107146176-A0305-02-0152-83
Figure 107146176-A0305-02-0153-84
<400> 32
Figure 107146176-A0305-02-0151-82
Figure 107146176-A0305-02-0152-83
Figure 107146176-A0305-02-0153-84

<210> 33 <210> 33

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 33

Figure 107146176-A0305-02-0154-85
Figure 107146176-A0305-02-0155-86
<400> 33
Figure 107146176-A0305-02-0154-85
Figure 107146176-A0305-02-0155-86

<210> 34 <210> 34

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 34

Figure 107146176-A0305-02-0155-87
Figure 107146176-A0305-02-0156-88
Figure 107146176-A0305-02-0157-89
<400> 34
Figure 107146176-A0305-02-0155-87
Figure 107146176-A0305-02-0156-88
Figure 107146176-A0305-02-0157-89

<210> 35 <210> 35

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 35

Figure 107146176-A0305-02-0157-90
Figure 107146176-A0305-02-0158-91
Figure 107146176-A0305-02-0159-92
Figure 107146176-A0305-02-0160-93
<400> 35
Figure 107146176-A0305-02-0157-90
Figure 107146176-A0305-02-0158-91
Figure 107146176-A0305-02-0159-92
Figure 107146176-A0305-02-0160-93

<210> 36 <210> 36

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 36

Figure 107146176-A0305-02-0160-94
Figure 107146176-A0305-02-0161-95
Figure 107146176-A0305-02-0162-96
<400> 36
Figure 107146176-A0305-02-0160-94
Figure 107146176-A0305-02-0161-95
Figure 107146176-A0305-02-0162-96

<210> 37 <210> 37

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 37

Figure 107146176-A0305-02-0162-97
Figure 107146176-A0305-02-0163-98
Figure 107146176-A0305-02-0164-99
Figure 107146176-A0305-02-0165-100
<400> 37
Figure 107146176-A0305-02-0162-97
Figure 107146176-A0305-02-0163-98
Figure 107146176-A0305-02-0164-99
Figure 107146176-A0305-02-0165-100

<210> 38 <210> 38

<211> 217 <211> 217

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 38

Figure 107146176-A0305-02-0165-101
Figure 107146176-A0305-02-0166-102
<400> 38
Figure 107146176-A0305-02-0165-101
Figure 107146176-A0305-02-0166-102

<210> 39 <210> 39

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 39

Figure 107146176-A0305-02-0166-103
Figure 107146176-A0305-02-0167-104
Figure 107146176-A0305-02-0168-105
Figure 107146176-A0305-02-0169-106
<400> 39
Figure 107146176-A0305-02-0166-103
Figure 107146176-A0305-02-0167-104
Figure 107146176-A0305-02-0168-105
Figure 107146176-A0305-02-0169-106

<210> 40 <210> 40

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 40

Figure 107146176-A0305-02-0169-107
Figure 107146176-A0305-02-0170-108
Figure 107146176-A0305-02-0171-109
<400> 40
Figure 107146176-A0305-02-0169-107
Figure 107146176-A0305-02-0170-108
Figure 107146176-A0305-02-0171-109

<210> 41 <210> 41

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 41

Figure 107146176-A0305-02-0171-110
Figure 107146176-A0305-02-0172-111
Figure 107146176-A0305-02-0173-112
Figure 107146176-A0305-02-0174-113
<400> 41
Figure 107146176-A0305-02-0171-110
Figure 107146176-A0305-02-0172-111
Figure 107146176-A0305-02-0173-112
Figure 107146176-A0305-02-0174-113

<210> 42 <210> 42

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 42

Figure 107146176-A0305-02-0174-114
Figure 107146176-A0305-02-0175-115
Figure 107146176-A0305-02-0176-116
<400> 42
Figure 107146176-A0305-02-0174-114
Figure 107146176-A0305-02-0175-115
Figure 107146176-A0305-02-0176-116

<210> 43 <210> 43

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 43

Figure 107146176-A0305-02-0176-117
Figure 107146176-A0305-02-0177-118
Figure 107146176-A0305-02-0178-119
Figure 107146176-A0305-02-0179-120
<400> 43
Figure 107146176-A0305-02-0176-117
Figure 107146176-A0305-02-0177-118
Figure 107146176-A0305-02-0178-119
Figure 107146176-A0305-02-0179-120

<210> 44 <210> 44

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 44

Figure 107146176-A0305-02-0179-121
Figure 107146176-A0305-02-0180-122
<400> 44
Figure 107146176-A0305-02-0179-121
Figure 107146176-A0305-02-0180-122

<210> 45 <210> 45

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 45

Figure 107146176-A0305-02-0180-123
Figure 107146176-A0305-02-0181-124
Figure 107146176-A0305-02-0182-125
<400> 45
Figure 107146176-A0305-02-0180-123
Figure 107146176-A0305-02-0181-124
Figure 107146176-A0305-02-0182-125

<210> 46 <210> 46

<211> 215 <211> 215

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 46

Figure 107146176-A0305-02-0183-126
Figure 107146176-A0305-02-0184-127
<400> 46
Figure 107146176-A0305-02-0183-126
Figure 107146176-A0305-02-0184-127

<210> 47 <210> 47

<211> 461 <211> 461

<212> PRT <212> PRT

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成胜肽 <223> Synthetic peptide

<400> 47

Figure 107146176-A0305-02-0184-128
Figure 107146176-A0305-02-0185-129
Figure 107146176-A0305-02-0186-130
<400> 47
Figure 107146176-A0305-02-0184-128
Figure 107146176-A0305-02-0185-129
Figure 107146176-A0305-02-0186-130

Claims (4)

一種呈CrossMab形式且能夠中和HIV的雙專一性抗體，其中該抗體包含與HIV套膜蛋白結合的第一抗體10E8v2.0之輕鏈及重鏈部分、及與細胞膜受體蛋白或細胞膜輔受體蛋白結合的第二抗體ibalizumab之輕鏈及重鏈部分，其中該第一抗體10E8v2.0之輕鏈部分包含SEQ ID NO：33的胺基酸序列，其中SEQ ID NO：33併入二個突變，該等突變係位於SEQ ID NO：33之胺基酸位置P40與I45的疏水性至親水性殘基突變，其中該等位置係基於Kabat編號系統；該第一抗體10E8v2.0之重鏈部分包含SEQ ID NO：34的胺基酸序列，其中SEQ ID NO：34併入四個突變，該等突變係位於胺基酸位置L72、I75、F77、與L108的疏水性至親水性殘基突變，其中該等位置係基於Kabat編號系統；該第二抗體ibalizumab之輕鏈部分包含SEQ ID NO：1的胺基酸序列，且該第二抗體ibalizumab之重鏈部分包含SEQ ID NO：2的胺基酸序列。 A bispecific antibody in the form of CrossMab and capable of neutralizing HIV, wherein the antibody comprises the light chain and heavy chain part of the first antibody 10E8v2.0 bound to the HIV mantle protein, and the cell membrane receptor protein or cell membrane co-receptor The light chain and heavy chain parts of the second antibody ibalizumab bound by body protein, wherein the light chain part of the first antibody 10E8v2.0 comprises the amino acid sequence of SEQ ID NO: 33, wherein SEQ ID NO: 33 is incorporated into two Mutations, the mutations are the hydrophobic to hydrophilic residue mutations at the amino acid positions P40 and I45 of SEQ ID NO: 33, wherein these positions are based on the Kabat numbering system; the heavy chain of the first antibody 10E8v2.0 The part contains the amino acid sequence of SEQ ID NO: 34, wherein SEQ ID NO: 34 incorporates four mutations, these mutations are located in the amino acid positions L72, I75, F77, and L108 hydrophobic to hydrophilic residues Mutation, wherein the positions are based on the Kabat numbering system; the light chain portion of the second antibody ibalizumab includes the amino acid sequence of SEQ ID NO: 1, and the heavy chain portion of the second antibody ibalizumab includes the amino acid sequence of SEQ ID NO: 2 Amino acid sequence. 如請求項1所述之雙專一性抗體，其中該等對於SEQ ID NO：33的突變係P40T及I45K，其中該等位置係基於Kabat編號系統。 The bispecific antibody according to claim 1, wherein the mutations to SEQ ID NO: 33 are P40T and I45K, and the positions are based on the Kabat numbering system. 一種醫藥組成物，其包含如請求項1所述之雙專一性抗體、及醫藥上可接受的載體。 A pharmaceutical composition comprising the bispecific antibody as described in claim 1 and a pharmaceutically acceptable carrier. 如請求項3所述之醫藥組成物，其中該組成物經調配以用於口服、鼻內、肺、皮內、透皮、皮下、肌內、腹膜內、或靜脈內遞送。The pharmaceutical composition according to claim 3, wherein the composition is formulated for oral, intranasal, pulmonary, intradermal, transdermal, subcutaneous, intramuscular, intraperitoneal, or intravenous delivery.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150152167A1 (en) * 2013-12-02 2015-06-04 Aaron Diamond Aids Research Center Hiv-1-neutralizing antibody potency and breadth via cell receptor anchoring using bispecific antibodies with native architecture

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104955847A (en) * 2012-12-04 2015-09-30 马里兰州大学(巴尔的摩) HIV-1 Env-binding antibodies, fusion proteins, and methods of use
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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Sormanni P et al., "Rapid and accurate in silico solubility screening of a monoclonal antibody library", Scientific Reports | 7: 8200 | DOI:10.1038/s41598-017-07800-w, 2017/08/15
Sormanni P et al., "Rapid and accurate in silico solubility screening of a monoclonal antibody library", Scientific Reports | 7: 8200 | DOI:10.1038/s41598-017-07800-w, 2017/08/15; *
Wu SJ et al., "Structure-based engineering of a monoclonal antibody for improved solubility", Protein Engineering, Design & Selection, vol.23 no.8 pp.643-651, 2010/06/11 *

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